|
1
|
Shah PA, Mazumdar T, Ghosh S, Yapindi L, Powell RT, Park YS, Shen L, Fernandez AM, Stephan CC, Wang J, Sikora AG, Kazi J, Frederick MJ, Johnson FM. Polo-like kinase 1 inactivation enhances PI3K inhibition-mediated apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma. Cancer Lett 2025; 625:217814. [PMID: 40412794 DOI: 10.1016/j.canlet.2025.217814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 05/05/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
PI3K inhibition causes apoptosis selectively in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR NOTCH1-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal in vitro methods and in two HNSCC xenograft models. Compound efficacy was enriched in 30 of 306 drug classes. Drugs from nine classes enhanced the cell killing of PI3K inhibition. We pursued experiments with PLK1 inhibitors based on clinical relevance and efficacy in parental and AR models. The combination of PLK1 and PI3K inhibition caused apoptosis, DNA damage, and immunogenic cell death in vitro and extended survival in vivo. PLK1 activity decreased following PI3K inhibition only in sensitive NOTCH1-mutant HNSCC cell lines and not in AR or resistant wild-type cells. The combination of PI3K and PLK1 inhibition causes robust killing of HNSCC and overcomes PI3K inhibitor resistance. Specific and well-tolerated PI3K and PLK1 inhibitors that do not have overlapping toxicity are in clinical development. We hypothesize that this combination may have a wide therapeutic window with significant efficacy but modest toxicity because it should spare normal cells that have wild-type NOTCH1 and are not sensitive to PI3K inhibition.
Collapse
Affiliation(s)
- Pooja A Shah
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tuhina Mazumdar
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Soma Ghosh
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lacin Yapindi
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Reid T Powell
- Center for Translational Cancer Research, Institute of Biosciences and Technology Texas A&M University College of Medicine, Houston, TX, USA
| | - Yong S Park
- Center for Translational Cancer Research, Institute of Biosciences and Technology Texas A&M University College of Medicine, Houston, TX, USA
| | - Li Shen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anne M Fernandez
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Clifford C Stephan
- Center for Translational Cancer Research, Institute of Biosciences and Technology Texas A&M University College of Medicine, Houston, TX, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Andrew G Sikora
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jawad Kazi
- Department of Otolaryngology, Baylor College of Medicine, Houston, TX, USA
| | | | - Faye M Johnson
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
| |
Collapse
|
|
2
|
Lin D, Xu Y, Zhan H, Liang Y, Liu R, Liu J, Luo D, Chen X, Cai J, Zou Y. Targeting the ZMYM2-ANXA9 Axis with FLT3 Inhibitor G749 Overcomes Oxaliplatin Resistance in Colorectal Cancer. Biomedicines 2025; 13:1247. [PMID: 40427072 DOI: 10.3390/biomedicines13051247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes associated with a poor response to neoadjuvant chemotherapy in CRC patients. Among 298 candidate genes, ANXA9 emerged as significantly overexpressed in chemoresistant tumors and associated with a poor prognosis. These findings were further validated in an independent cohort of 146 Stage III CRC patients using immunohistochemistry and survival analysis. The expression of ANXA9 was evaluated in oxaliplatin acquired-resistant CRC cell lines via qPCR and Western blot. Functional studies, including RNA interference, colony formation, apoptosis assays, and drug sensitivity testing, were performed in vitro and in vivo to assess the role of ANXA9. A high-throughput drug screen identified G749, a FLT3 inhibitor, as a potential therapeutic agent. Results:ANXA9 expression was significantly elevated in non-responders to chemotherapy and oxaliplatin-resistant CRC cell lines. The knockdown of ANXA9 reduced proliferation and enhanced oxaliplatin sensitivity. G749 was found to suppress ANXA9 expression in a dose-dependent manner and inhibit CRC cell growth in vitro and in patient-derived organoids. In a CRC xenograft mouse model, G749 reduced the tumor burden without observable toxicity. Mechanistically, we identified ZMYM2 as a transcriptional regulator of ANXA9. ChIP-qPCR confirmed ZMYM2 binding to the ANXA9 promoter, especially in resistant cells. Silencing ZMYM2 suppressed tumor cell growth and restored chemosensitivity. Conclusions: The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC.
Collapse
Affiliation(s)
- Dezheng Lin
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Yucheng Xu
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Huanmiao Zhan
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Yufan Liang
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China
| | - Riyun Liu
- Department of Clinical Medicine, The Sixth Clinical School of Guangzhou Medical University, Guangzhou 511436, China
| | - Jun Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Dandong Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Xiaochuan Chen
- Department of Obstetrics and Gynecology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Jiawei Cai
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| | - Yifeng Zou
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 515000, China
| |
Collapse
|
|
3
|
Li P, Zhao Y, Lu M, Chen C, Li Y, Wang L, Zeng S, Peng Y, Liang H, Zhang G. Pharmacological inhibition of PLK1/PRC1 triggers mitotic catastrophe and sensitizes lung cancers to chemotherapy. Cell Death Dis 2025; 16:374. [PMID: 40355412 PMCID: PMC12069692 DOI: 10.1038/s41419-025-07708-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 04/24/2025] [Accepted: 05/01/2025] [Indexed: 05/14/2025]
Abstract
Polo-like kinase 1 (PLK1) signaling drives tumor malignancy and chemotherapy resistance, which is an unmet clinical need. Recruiting PLK1 to the central spindle during anaphase is necessary for its function in promoting cancer cell proliferation, which is achieved by binding to microtubule-associated protein regulating of cytokinesis (PRC1) located in the spindle. However, the role of PLK1/PRC1 signaling in chemotherapy resistance is unknown. In this study, we identified a small molecule B4 which inhibited PLK1/PRC1 signaling through disrupting the formation of PLK1/PRC1 protein complexes. In the presence of blocking PLK1/PRC1 signaling, enhanced sensitivity of drug-resistant tumors to traditional chemotherapy was found. Suppression of PLK1 activity by B4 inhibited disease progression in allograft models, and combination with cisplatin elicited dramatic regression of drug-resistant tumors. Our findings provide a promising strategy to target the PLK1 signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in non-small cell lung cancer (NSCLC).
Collapse
Affiliation(s)
- Pingping Li
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Yufei Zhao
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Minghan Lu
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Chengfei Chen
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Yongkun Li
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Lingling Wang
- School of Comprehensive Health Management, Xihua University, Chengdu, China
| | - Shulan Zeng
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Yan Peng
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Hong Liang
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Guohai Zhang
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
- Joint Medical Research Center of Guangxi Normal University & Guilin Hospital of Chinese Traditional and Western Medicine, Guilin, China.
| |
Collapse
|
|
4
|
Loycano MA, Pienta KJ, Amend SR. Temporal myc dynamics permit mitotic bypass, promoting polyploid phenotypes. Cancer Lett 2025; 613:217526. [PMID: 39909233 PMCID: PMC11924244 DOI: 10.1016/j.canlet.2025.217526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/29/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
High Myc phenotypes are extensively documented in the hyperproliferative cell cycle of cancer cells, as well as non-proliferative endoreplication cycles engaged during normal development and stress response. Notably, endoreplication in cancer produces chemotherapy resistant polyploid cells, necessitating a clearer understanding of altered cell cycle regulation that uncouples DNA replication and mitotic cell division. The c-Myc oncogene is a well-established transcriptional regulator of cell cycle progression and has been extensively published as an essential driver of the G1/S transition. Beyond S phase, Myc transcriptionally activates the proteins that drive mitotic entry. Sustained activation of Myc through the cell cycle transcriptionally couples DNA replication and mitotic cell division. Based on the literature in this field, we propose a new model of temporal regulation of Myc activity that serves to either couple or uncouple these two processes, determining cell cycle fate - proliferation or polyploidy. The mitotic cell cycle requires two pulses of Myc activity - the first driving the G1/S transition and the second driving the G2/M transition. During mitosis, Myc activity must be silenced to achieve high-fidelity division. Absence of the second activity pulse during G2 results in the downregulation of the proteins essential for mitotic entry and permits premature activation of APC/C, inducing mitotic bypass. A subsequent rise of Myc activity following mitotic bypass permits genome re-replication, driving polyploid phenotypes. This model serves to provide a new level of understanding to the global regulation of S phase-mitosis coupling, as well as a new lens to view low Myc phenotypes.
Collapse
Affiliation(s)
- Michael A Loycano
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Kenneth J Pienta
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Sarah R Amend
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
5
|
Xiang X, Shuya P, Jiamin Z, Zihan Z, Xumei Y, Jingjin L. 3-Phosphoinositide-Dependent Kinase 1 as a Therapeutic Target for Treating Diabetes. Curr Diabetes Rev 2025; 21:47-56. [PMID: 38468518 DOI: 10.2174/0115733998278669240226061329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/09/2024] [Accepted: 01/30/2024] [Indexed: 03/13/2024]
Abstract
The role of 3-phosphoinositide-dependent kinase 1 (PDK1) has been welldocumented in the development of diabetes. This review offers a thorough examination of its composition and associated routes, specifically focusing on insulin signaling and glucose processing. By examining the precise connection between PDK1 and diabetes, various strategies specifically targeting PDK1 were also investigated. Additionally, recent discoveries from mouse models were compiled where PDK1 was knocked out in certain tissues, which demonstrated encouraging outcomes for focused treatments despite the absence of any currently approved clinical PDK1 activators. Moreover, the dual nature of PDK1 activation was discussed, encompassing both anti-diabetic and pro-oncogenic effects. Hence, the development of a PDK1 modifier is of utmost importance, as it can activate anti-diabetic pathways while inhibiting pro-oncogenic pathways, thus aiding in the treatment of diabetes. In general, PDK1 presents a noteworthy opportunity for future therapeutic strategies in the treatment of diabetes.
Collapse
Affiliation(s)
- Xie Xiang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Childrens' Hospital of Wenzhou Medical University, Wenzhou, Zhejieng 325027, China
- Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejieng 325027, China
| | - Pan Shuya
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejieng, China
| | - Zhang Jiamin
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejieng, China
| | - Zhang Zihan
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejieng, China
| | - Yang Xumei
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Childrens' Hospital of Wenzhou Medical University, Wenzhou, Zhejieng 325027, China
- Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejieng 325027, China
| | - Liu Jingjin
- Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| |
Collapse
|
|
6
|
Liu S, Deng P, Yu Z, Hong JH, Gao J, Huang Y, Xiao R, Yin J, Zeng X, Sun Y, Wang P, Geng R, Chan JY, Guan P, Yu Q, Teh B, Jiang Q, Xia X, Xiong Y, Chen J, Huo Y, Tan J. CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403782. [PMID: 39412086 PMCID: PMC11615783 DOI: 10.1002/advs.202403782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 10/01/2024] [Indexed: 12/06/2024]
Abstract
Poly (ADP-ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high-throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti-tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response is triggered through the induction of the cGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi.
Collapse
Affiliation(s)
- Shini Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
- Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesSchool of MedicineSouthern Medical UniversityGuangzhouGuangdong510080P. R. China
| | - Peng Deng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
- Biotherapy CenterSun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhou510120P. R. China
| | - Zhaoliang Yu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Jing Han Hong
- Cancer and Stem Cell Biology ProgramDuke‐NUS Medical SchoolSingapore169857Singapore
| | - Jiuping Gao
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yulin Huang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Rong Xiao
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Jiaxin Yin
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Xian Zeng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yichen Sun
- Department of Laboratory MedicineGuangzhou First People's HospitalSchool of MedicineSouth China University of TechnologyGuangzhou510180P. R. China
| | - Peili Wang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Ruizi Geng
- Experimental Animal CenterGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou511436P. R. China
| | - Jason Yongsheng Chan
- Division of Medical SciencesLaboratory of Cancer EpigenomeNational Cancer Centre SingaporeSingapore169610Singapore
| | - Peiyong Guan
- Genome Institute of SingaporeA*STARSingapore138672Singapore
| | - Qiang Yu
- Cancer and Stem Cell Biology ProgramDuke‐NUS Medical SchoolSingapore169857Singapore
- Genome Institute of SingaporeA*STARSingapore138672Singapore
| | - Bin‐Tean Teh
- Cancer and Stem Cell Biology ProgramDuke‐NUS Medical SchoolSingapore169857Singapore
- Division of Medical SciencesLaboratory of Cancer EpigenomeNational Cancer Centre SingaporeSingapore169610Singapore
- Genome Institute of SingaporeA*STARSingapore138672Singapore
| | - Qingping Jiang
- Department of PatholgyGuangdong Provincial Key Laboratory of Major Obstetric DiseaseThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong510150China
| | - Xiaojun Xia
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Ying Xiong
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Jianfeng Chen
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yongliang Huo
- Experimental Animal CenterGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou511436P. R. China
| | - Jing Tan
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
- Division of Medical SciencesLaboratory of Cancer EpigenomeNational Cancer Centre SingaporeSingapore169610Singapore
- Hainan Academy of Medical ScienceHainan Medical UniversityHaikou571199P. R. China
| |
Collapse
|
|
7
|
Li P, Li Y, Ma X, Li L, Zeng S, Peng Y, Liang H, Zhang G. Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells. Eur J Med Chem 2024; 271:116416. [PMID: 38657480 DOI: 10.1016/j.ejmech.2024.116416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/26/2024]
Abstract
Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 μM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.
Collapse
Affiliation(s)
- Pingping Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Yongkun Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Xuesong Ma
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Liangping Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Shulan Zeng
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Yan Peng
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Hong Liang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China.
| | - Guohai Zhang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China.
| |
Collapse
|
|
8
|
Streeter SA, Williams AG, Evans JR, Wang J, Guarnaccia AD, Florian AC, Al-Tobasei R, Liu Q, Tansey WP, Weissmiller AM. Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus. BMC Genomics 2024; 25:360. [PMID: 38605297 PMCID: PMC11007937 DOI: 10.1186/s12864-024-10282-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 04/03/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5-a critical MYC cofactor-regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. RESULTS Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. CONCLUSIONS Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
Collapse
Affiliation(s)
- Sarah A Streeter
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 37132, USA
| | - Alexandria G Williams
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 37132, USA
| | - James R Evans
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 37132, USA
| | - Jing Wang
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA
| | - Alissa D Guarnaccia
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, 94080, USA
| | - Andrea C Florian
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA
- Department of Biology, Belmont University, Nashville, TN, 37212, USA
| | - Rafet Al-Tobasei
- Department of Computer Science, Middle Tennessee State University, Murfreesboro, TN, 32132, USA
| | - Qi Liu
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA
| | - William P Tansey
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA
| | - April M Weissmiller
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 37132, USA.
| |
Collapse
|
|
9
|
Yu Z, Deng P, Chen Y, Lin D, Liu S, Hong J, Guan P, Chen J, Zhong ME, Chen J, Chen X, Sun Y, Wang Y, Wang P, Cai Z, Chan JY, Huang Y, Xiao R, Guo Y, Zeng X, Wang W, Zou Y, Yu Q, Lan P, Teh BT, Wu X, Tan J. Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer. Proc Natl Acad Sci U S A 2024; 121:e2304619121. [PMID: 38289962 PMCID: PMC10861914 DOI: 10.1073/pnas.2304619121] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 11/29/2023] [Indexed: 02/01/2024] Open
Abstract
Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.
Collapse
Affiliation(s)
- Zhaoliang Yu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Peng Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Yufeng Chen
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Dezheng Lin
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510060, People’s Republic of China
| | - Shini Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Jinghan Hong
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Medical School, Singapore169857, Singapore
| | - Peiyong Guan
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Medical School, Singapore169857, Singapore
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore138672, Singapore
| | - Jianfeng Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Min-er Zhong
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Jinghong Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Xiaochuan Chen
- Department of Obstetrics and Gynecology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Yichen Sun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Yali Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Peili Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Zerong Cai
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Jason Yongsheng Chan
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore169610, Singapore
| | - Yulin Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Rong Xiao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Yaoyu Guo
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Xian Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
| | - Wenyu Wang
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Yifeng Zou
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Qiang Yu
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Medical School, Singapore169857, Singapore
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore138672, Singapore
| | - Ping Lan
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Bin Tean Teh
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Medical School, Singapore169857, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore169610, Singapore
| | - Xiaojian Wu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong510655, People’s Republic of China
| | - Jing Tan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong510060, People’s Republic of China
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore169610, Singapore
| |
Collapse
|
|
10
|
Wang Y, Yao M, Li C, Yang K, Qin X, Xu L, Shi S, Yu C, Meng X, Xie C. Targeting ST8SIA6-AS1 counteracts KRAS G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling. Exp Hematol Oncol 2023; 12:105. [PMID: 38104151 PMCID: PMC10724920 DOI: 10.1186/s40164-023-00466-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. METHODS By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. RESULTS KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. CONCLUSIONS Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
Collapse
Affiliation(s)
- Yafang Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
| | - Mingyue Yao
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Cheng Li
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Kexin Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiaolong Qin
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Lansong Xu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Shangxuan Shi
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Chengcheng Yu
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiangjun Meng
- Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
- China Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai, 200001, China
- China Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200001, China
| | - Chengying Xie
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China.
| |
Collapse
|
|
11
|
Katsuragawa‐Taminishi Y, Mizutani S, Kawaji‐Kanayama Y, Onishi A, Okamoto H, Isa R, Mizuhara K, Muramatsu A, Fujino T, Tsukamoto T, Shimura Y, Taniwaki M, Miyagawa‐Hayashino A, Konishi E, Kuroda J. Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas. Cancer Sci 2023; 114:4691-4705. [PMID: 37840379 PMCID: PMC10728023 DOI: 10.1111/cas.15995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/09/2023] [Accepted: 10/03/2023] [Indexed: 10/17/2023] Open
Abstract
B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL-derived cell lines examined, including those from activated B-cell-like diffuse large B-cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient-derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.
Collapse
Affiliation(s)
- Yoko Katsuragawa‐Taminishi
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Shinsuke Mizutani
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Yuka Kawaji‐Kanayama
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Akio Onishi
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Haruya Okamoto
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Reiko Isa
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Kentaro Mizuhara
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Ayako Muramatsu
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Takahiro Fujino
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Taku Tsukamoto
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | - Yuji Shimura
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
- Department of Blood TransfusionKyoto Prefectural University of MedicineKyotoJapan
| | - Masafumi Taniwaki
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| | | | - Eiichi Konishi
- Department of Surgical PathologyKyoto Prefectural University of MedicineKyotoJapan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of MedicineKyotoJapan
| |
Collapse
|
|
12
|
Bhin J, Yemelyanenko J, Chao X, Klarenbeek S, Opdam M, Malka Y, Hoekman L, Kruger D, Bleijerveld O, Brambillasca CS, Sprengers J, Siteur B, Annunziato S, van Haren MJ, Martin NI, van de Ven M, Peters D, Agami R, Linn SC, Boven E, Altelaar M, Jonkers J, Zingg D, Wessels LF. MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer. J Exp Med 2023; 220:e20211743. [PMID: 37642941 PMCID: PMC10465700 DOI: 10.1084/jem.20211743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 05/18/2023] [Accepted: 07/24/2023] [Indexed: 08/31/2023] Open
Abstract
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.
Collapse
Affiliation(s)
- Jinhyuk Bhin
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
- Department of Biomedical System Informatics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Julia Yemelyanenko
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Xue Chao
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Sjoerd Klarenbeek
- Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Mark Opdam
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Yuval Malka
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Liesbeth Hoekman
- Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Dinja Kruger
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam/Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Onno Bleijerveld
- Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Chiara S. Brambillasca
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Justin Sprengers
- Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Bjørn Siteur
- Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Stefano Annunziato
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Matthijs J. van Haren
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden, Netherlands
| | - Nathaniel I. Martin
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden, Netherlands
| | - Marieke van de Ven
- Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Dennis Peters
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Reuven Agami
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Sabine C. Linn
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Epie Boven
- Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam/Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Maarten Altelaar
- Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
- Netherlands Proteomics Centre, Utrecht, Netherlands
| | - Jos Jonkers
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Daniel Zingg
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Lodewyk F.A. Wessels
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| |
Collapse
|
|
13
|
Zheng N, Wei J, Wu D, Xu Y, Guo J. Master kinase PDK1 in tumorigenesis. Biochim Biophys Acta Rev Cancer 2023; 1878:188971. [PMID: 37640147 DOI: 10.1016/j.bbcan.2023.188971] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/13/2023] [Accepted: 08/05/2023] [Indexed: 08/31/2023]
Abstract
3-phosphoinositide-dependent protein kinase 1 (PDK1) is considered as master kinase regulating AGC kinase family members such as AKT, SGK, PLK, S6K and RSK. Although autophosphorylation regulates PDK1 activity, accumulating evidence suggests that PDK1 is manipulated by many other mechanisms, including S6K-mediated phosphorylation, and the E3 ligase SPOP-mediated ubiquitination and degradation. Dysregulation of these upstream regulators or downstream signals involves in cancer development, as PDK1 regulating cell growth, metastasis, invasion, apoptosis and survival time. Meanwhile, overexpression of PDK1 is also exposed in a plethora of cancers, whereas inhibition of PDK1 reduces cell size and inhibits tumor growth and progression. More importantly, PDK1 also modulates the tumor microenvironments and markedly influences tumor immunotherapies. In summary, we comprehensively summarize the downstream signals, upstream regulators, mouse models, inhibitors, tumor microenvironment and clinical treatments for PDK1, and highlight PDK1 as a potential cancer therapeutic target.
Collapse
Affiliation(s)
- Nana Zheng
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Jiaqi Wei
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China.
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China.
| | - Jianping Guo
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
| |
Collapse
|
|
14
|
Han D, Wang W, Jeon JH, Shen T, Huang X, Yi P, Dong B, Yang F. Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy. PLoS Biol 2023; 21:e3002227. [PMID: 37531320 PMCID: PMC10395914 DOI: 10.1371/journal.pbio.3002227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 06/30/2023] [Indexed: 08/04/2023] Open
Abstract
Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.
Collapse
Affiliation(s)
- Dong Han
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Wei Wang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Julie Heejin Jeon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Tao Shen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Xiangsheng Huang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Ping Yi
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Bingning Dong
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Feng Yang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America
| |
Collapse
|
|
15
|
Liu S, Xiang Y, Wang B, Gao C, Chen Z, Xie S, Wu J, Liu Y, Zhao X, Yang C, Yue Z, Wang L, Wen X, Zhang R, Zhang F, Xu H, Zhai X, Zheng H, Zhang H, Qian M. USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/LDHA axis. Blood Adv 2023; 7:3099-3112. [PMID: 36912760 PMCID: PMC10362547 DOI: 10.1182/bloodadvances.2022008284] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 02/03/2023] [Accepted: 02/12/2023] [Indexed: 03/14/2023] Open
Abstract
The effect of aerobic glycolysis remains elusive in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of deubiquitination is involved in glycolysis, by targeting glycolytic rate-limiting enzymes. Here, we demonstrated that upregulated deubiquitinase ubiquitin-specific peptidase 1 (USP1) expression correlated with poor prognosis in pediatric primary T-ALL samples. USP1 depletion abolished cellular proliferation and attenuated glycolytic metabolism. In vivo experiments showed that USP1 suppression decreased leukemia progression in nude mice. Inhibition of USP1 caused a decrease in both mRNA and protein levels in lactate dehydrogenase A (LDHA), a critical glycolytic enzyme. Moreover, USP1 interacted with and deubiquitinated polo-like kinase 1 (PLK1), a critical regulator of glycolysis. Overexpression of USP1 with upregulated PLK1 was observed in most samples of patients with T-ALL. In addition, PLK1 inhibition reduced LDHA expression and abrogated the USP1-mediated increase of cell proliferation and lactate level. Ectopic expression of LDHA can rescue the suppressive effect of USP1 silencing on cell growth and lactate production. Pharmacological inhibition of USP1 by ML323 exhibited cell cytotoxicity in human T-ALL cells. Taken together, our results demonstrated that USP1 may be a promising therapeutic target in pediatric T-ALL.
Collapse
Affiliation(s)
- Shuguang Liu
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Yuening Xiang
- Institute of Pediatrics and Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Boshi Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Gao
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Zhenping Chen
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Shao Xie
- Institute of Pediatrics and Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jing Wu
- Institute of Pediatrics and Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yi Liu
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xiaoxi Zhao
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Chao Yang
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Zhixia Yue
- Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Linya Wang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xiaojia Wen
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Ruidong Zhang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Feng Zhang
- Center for Precision Medicine, Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
| | - Heng Xu
- Division of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaowen Zhai
- Department of Hematology and Oncology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China
| | - Huyong Zheng
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Hui Zhang
- Department of Hematology & Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Hematology & Oncology, Fujian Branch of Shanghai Children’s Medical Center, Fujian Children’s Hospital, Fuzhou, China
| | - Maoxiang Qian
- Institute of Pediatrics and Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
16
|
Accattatis FM, Caruso A, Carleo A, Del Console P, Gelsomino L, Bonofiglio D, Giordano C, Barone I, Andò S, Bianchi L, Catalano S. CEBP-β and PLK1 as Potential Mediators of the Breast Cancer/Obesity Crosstalk: In Vitro and In Silico Analyses. Nutrients 2023; 15:2839. [PMID: 37447165 DOI: 10.3390/nu15132839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Over the last two decades, obesity has reached pandemic proportions in several countries, and expanding evidence is showing its contribution to several types of malignancies, including breast cancer (BC). The conditioned medium (CM) from mature adipocytes contains a complex of secretes that may mimic the obesity condition in studies on BC cell lines conducted in vitro. Here, we report a transcriptomic analysis on MCF-7 BC cells exposed to adipocyte-derived CM and focus on the predictive functional relevance that CM-affected pathways/processes and related biomarkers (BMs) may have in BC response to obesity. CM was demonstrated to increase cell proliferation, motility and invasion as well as broadly alter the transcript profiles of MCF-7 cells by significantly modulating 364 genes. Bioinformatic functional analyses unraveled the presence of five highly relevant central hubs in the direct interaction networks (DIN), and Kaplan-Meier analysis sorted the CCAAT/enhancer binding protein beta (CEBP-β) and serine/threonine-protein kinase PLK1 (PLK1) as clinically significant biomarkers in BC. Indeed, CEBP-β and PLK1 negatively correlated with BC overall survival and were up-regulated by adipocyte-derived CM. In addition to their known involvement in cell proliferation and tumor progression, our work suggests them as a possible "deus ex machina" in BC response to fat tissue humoral products in obese women.
Collapse
Affiliation(s)
- Felice Maria Accattatis
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Amanda Caruso
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Alfonso Carleo
- Department of Pulmonology, Hannover Medical School, Carl-Neuberg-Straße, 30625 Hannover, Germany
| | - Piercarlo Del Console
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Laura Bianchi
- Section of Functional Proteomics, Department of Life Sciences, Via Aldo Moro, University of Siena, 53100 Siena, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| |
Collapse
|
|
17
|
Borkowsky S, Gass M, Alavizargar A, Hanewinkel J, Hallstein I, Nedvetsky P, Heuer A, Krahn MP. Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK. Cells 2023; 12:cells12050812. [PMID: 36899949 PMCID: PMC10000615 DOI: 10.3390/cells12050812] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1's kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth.
Collapse
Affiliation(s)
- Sarah Borkowsky
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
| | - Maximilian Gass
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
| | - Azadeh Alavizargar
- Institute of Physical Chemistry, University of Münster, Corrensstr. 28/30, 48149 Münster, Germany
| | - Johannes Hanewinkel
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
| | - Ina Hallstein
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
| | - Pavel Nedvetsky
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
| | - Andreas Heuer
- Institute of Physical Chemistry, University of Münster, Corrensstr. 28/30, 48149 Münster, Germany
| | - Michael P. Krahn
- Medical Cell Biology, Medical Clinic D, University Hospital of Münster, Albert-Schweitzer Campus 1-A14, 48149 Münster, Germany
- Correspondence: ; Tel.: +49-251-8357052
| |
Collapse
|
|
18
|
Boi D, Rubini E, Breccia S, Guarguaglini G, Paiardini A. When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases. Int J Mol Sci 2023; 24:4746. [PMID: 36902175 PMCID: PMC10003727 DOI: 10.3390/ijms24054746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Myc transcription factors are key regulators of many cellular processes, with Myc target genes crucially implicated in the management of cell proliferation and stem pluripotency, energy metabolism, protein synthesis, angiogenesis, DNA damage response, and apoptosis. Given the wide involvement of Myc in cellular dynamics, it is not surprising that its overexpression is frequently associated with cancer. Noteworthy, in cancer cells where high Myc levels are maintained, the overexpression of Myc-associated kinases is often observed and required to foster tumour cells' proliferation. A mutual interplay exists between Myc and kinases: the latter, which are Myc transcriptional targets, phosphorylate Myc, allowing its transcriptional activity, highlighting a clear regulatory loop. At the protein level, Myc activity and turnover is also tightly regulated by kinases, with a finely tuned balance between translation and rapid protein degradation. In this perspective, we focus on the cross-regulation of Myc and its associated protein kinases underlying similar and redundant mechanisms of regulation at different levels, from transcriptional to post-translational events. Furthermore, a review of the indirect effects of known kinase inhibitors on Myc provides an opportunity to identify alternative and combined therapeutic approaches for cancer treatment.
Collapse
Affiliation(s)
- Dalila Boi
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisabetta Rubini
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Sara Breccia
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Giulia Guarguaglini
- Institute of Molecular Biology and Pathology, National Research Council of Italy, Sapienza University of Rome, 00185 Rome, Italy
| | - Alessandro Paiardini
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| |
Collapse
|
|
19
|
The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity. Drug Resist Updat 2023; 66:100909. [PMID: 36525936 DOI: 10.1016/j.drup.2022.100909] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/27/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022]
Abstract
Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.
Collapse
|
|
20
|
Wang MW, Li Z, Chen LH, Wang N, Hu JM, Du J, Pang LJ, Qi Y. Polo-like kinase 1 as a potential therapeutic target and prognostic factor for various human malignancies: A systematic review and meta-analysis. Front Oncol 2022; 12:917366. [DOI: 10.3389/fonc.2022.917366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 10/06/2022] [Indexed: 11/16/2022] Open
Abstract
ObjectiveThe overexpression of polo-like kinase 1 (PLK-1) has been found in a broad spectrum of human tumors, making it an attractive prognostic tumor biomarker. Nowadays, PLK-1 is considered a cancer therapeutic target with clinical therapeutic value. The aim of the present study was to systematically review the prognostic and therapeutic value of PLK-1 in different malignant neoplasms.MethodsA systematic literature search of the Cochrane Library, PubMed, Web of Science, and China National Knowledge Internet (CNKI) databases was conducted between December 2018 and September 2022. In total, 41 published studies were screened, comprising 5,301 patients. We calculated the pooled odds ratios (ORs) and corresponding 95%CIs for the clinical parameters of patients included in these studies, as well as the pooled hazard ratios (HRs) and corresponding 95% CIs for 5-year overall survival (OS).ResultsOur analysis included 41 eligible studies, representing a total of 5,301 patients. The results showed that overexpression of PLK-1 was significantly associated with poor OS (HR, 1.57; 95% CI, 1.18–2.08) and inferior 5-year disease-free survival/relapse-free survival ((HR, 1.89; 95% CI, 1.47–2.44). The pooled analysis showed that PLK-1 overexpression was significantly associated with lymph node metastasis, histological grade, clinical stages (p < 0.001 respectively), and tumor grade (p < 0.001). In digestive system neoplasms, PLK-1 overexpression was significantly associated with histopathological classification, primary tumor grade, histological grade, and clinical stages (p = 0.002, p = 0.001, p < 0.0001, respectively). In breast cancer, PLK-1 was significantly associated with 5-year overall survival, histological grade, and lymph node metastasis (p < 0.001, p = 0.003, p < 0.001, respectively). In the female reproductive system, PLK-1 was significantly associated with clinical stage (p = 0.011). In the respiratory system, PLK-1 was significantly associated with clinical stage (p = 0.021).ConclusionOur analysis indicates that high PLK-1 expression is associated with aggressiveness and poor prognosis in malignant neoplasms. Therefore, PLK-1 may be a clinically valuable target for cancer treatment.
Collapse
|
|
21
|
Beyond controlling cell size: functional analyses of S6K in tumorigenesis. Cell Death Dis 2022; 13:646. [PMID: 35879299 PMCID: PMC9314331 DOI: 10.1038/s41419-022-05081-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 01/21/2023]
Abstract
As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.
Collapse
|
|
22
|
Zhang J, Zhang L, Wang J, Ouyang L, Wang Y. Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential. J Med Chem 2022; 65:10133-10160. [PMID: 35878418 DOI: 10.1021/acs.jmedchem.2c00614] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Polo-like kinase 1 (PLK1) plays an important role in a variety of cellular functions, including the regulation of mitosis, DNA replication, autophagy, and the epithelial-mesenchymal transition (EMT). PLK1 overexpression is often associated with cell proliferation and poor prognosis in cancer patients, making it a promising antitumor target. To date, at least 10 PLK1 inhibitors (PLK1i) have been entered into clinical trials, among which the typical kinase domain (KD) inhibitor BI 6727 (volasertib) was granted "breakthrough therapy designation" by the FDA in 2013. Unfortunately, many other KD inhibitors showed poor specificity, resulting in dose-limiting toxicity, which has greatly impeded their development. Researchers recently discovered many PLK1i with higher selectivity, stronger potency, and better absorption, distribution, metabolism, and elimination (ADME) characteristics. In this review, we emphasize the structure-activity relationships (SARs) of PLK1i, providing insights into new drugs targeting PLK1 for antitumor clinical practice.
Collapse
Affiliation(s)
- Jifa Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.,State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Lele Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.,State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis 38163, Tennessee, United States
| | - Liang Ouyang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.,State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.,State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| |
Collapse
|
|
23
|
Cai W, Nguyen MQ, Wilski NA, Purwin TJ, Vernon M, Tiago M, Aplin AE. A Genome-Wide Screen Identifies PDPK1 as a Target to Enhance the Efficacy of MEK1/2 Inhibitors in NRAS Mutant Melanoma. Cancer Res 2022; 82:2625-2639. [PMID: 35657206 PMCID: PMC9298960 DOI: 10.1158/0008-5472.can-21-3217] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 01/21/2023]
Abstract
Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for patients with NRAS mutant melanoma. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacologic and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent allograft model, PDPK1i+MEKi increased the ratio of intratumoral CD8+ T cells, delayed tumor growth, and prolonged survival; the combination treatment was less effective against tumors in immune-deficient mice. These data suggest PDPK1i+MEKi as an efficient immunostimulatory strategy against NRAS mutant melanoma. SIGNIFICANCE Targeting PDPK1 stimulates antitumor immunity and sensitizes NRAS mutant melanoma to MEK inhibition, providing rationale for the clinical development of a combinatorial approach for treating patients with melanoma.
Collapse
Affiliation(s)
- Weijia Cai
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Mai Q. Nguyen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Nicole A. Wilski
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Timothy J. Purwin
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Megane Vernon
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Manoela Tiago
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Andrew E. Aplin
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| |
Collapse
|
|
24
|
Helicobacter pylori promotes gastric cancer progression through the tumor microenvironment. Appl Microbiol Biotechnol 2022; 106:4375-4385. [PMID: 35723694 DOI: 10.1007/s00253-022-12011-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 02/05/2023]
Abstract
Gastric cancer (GC) is a leading type of cancer. Although immunotherapy has yielded important recent progress in the treatment of GC, the prognosis remains poor due to drug resistance and frequent recurrence and metastasis. There are multiple known risk factors for GC, and infection with Helicobacter pylori is one of the most significant. The mechanisms underlying the associations of H. pylori and GC remain unclear, but it is well known that infection can alter the tumor microenvironment (TME). The TME and the tumor itself constitute a complete ecosystem, and the TME plays critical roles in tumor progression, metastasis, and drug resistance. H. pylori infection can act synergistically with the TME to cause DNA damage and abnormal expression of multiple genes and activation of signaling pathways. It also modulates the host immune system in ways that enhance the proliferation and metastasis of tumor cells, promote epithelial-mesenchymal transition, inhibit apoptosis, and provide energy support for tumor growth. This review elaborates myriad ways that H. pylori infections promote the occurrence and progression of GC by influencing the TME, providing new directions for immunotherapy treatments for this important disease. KEY POINTS: • H. pylori infections cause DNA damage and affect the repair of the TME to DNA damage. • H. pylori infections regulate oncogenes or activate the oncogenic signaling pathways. • H. pylori infections modulate the immune system within the TME.
Collapse
|
|
25
|
Targeting protein kinases in cancer stem cells. Essays Biochem 2022; 66:399-412. [PMID: 35607921 DOI: 10.1042/ebc20220002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/01/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are subpopulations of cancer cells within the tumor bulk that have emerged as an attractive therapeutic target for cancer therapy. Accumulating evidence has shown the critical involvement of protein kinase signaling pathways in driving tumor development, cancer relapse, metastasis, and therapeutic resistance. Given that protein kinases are druggable targets for cancer therapy, tremendous efforts are being made to target CSCs with kinase inhibitors. In this review, we summarize the current knowledge and overview of the roles of protein kinases in various signaling pathways in CSC regulation and drug resistance. Furthermore, we provide an update on the preclinical and clinical studies for the use of kinase inhibitors alone or in combination with current therapies for effective cancer therapy. Despite great premises for the use of kinase inhibitors against CSCs, further investigations are needed to evaluate their efficiencies without any adverse effects on normal stem cells.
Collapse
|
|
26
|
RGS20 Promotes Tumor Progression through Modulating PI3K/AKT Signaling Activation in Penile Cancer. JOURNAL OF ONCOLOGY 2022; 2022:1293622. [PMID: 35498542 PMCID: PMC9042636 DOI: 10.1155/2022/1293622] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 11/20/2022]
Abstract
Regulator of G protein signaling 20 (RGS20) plays an important role in regulating neuronal G protein-coupled receptor signaling; however, its expression and oncogenic function in penile cancer (PC) remains unclear. Here, we observed high RGS20 expression in PC tissues compared to normal/adjacent penile tissues, which was closely associated with tumor stage, nodal status, and pelvic metastasis in our PC cohort. The cellular functional analysis of RGS20 revealed that manipulation of the RGS20 expression markedly affected cell viability, BrdU incorporation, soft agar clonogenesis, caspase-3 activity, and cell migration/invasion in PC cell models. Moreover, RGS20 could interact with PI3K p85α subunit and regulate PI3K/AKT signaling activation in PC cell lines. Knockdown of the PI3K p85α or p110α subunit attenuated cell viability, BrdU incorporation, soft agar clonogenesis, and cell migration/invasion in PC cell lines. In contrast, the overexpression of constitutively activated PI3K p110α mutant restored cell proliferation and cell migration/invasion caused by RGS20 depletion in PC cells. Consistent with the in vitro findings, RGS20 depletion attenuated PI3K/AKT signaling activation and suppressed tumor growth in a murine xenograft model. Importantly, the high RGS20 expression was associated with PI3K/AKT signaling activation and unfavorable progression-free/overall survival, highlighting the clinical relevance of RGS20/PI3K/AKT signaling in PC. In conclusion, the aberrant RGS20 expression may serve as a diagnostic and prognostic marker for PC. RGS20 may promote PC progression through modulating PI3K/AKT signaling activation, which may assist with the development of RGS20-targeting therapeutics in the future.
Collapse
|
|
27
|
Gao P, Hao JL, Xie QW, Han GQ, Xu BB, Hu H, Sa NE, Du XW, Tang HL, Yan J, Dong XM. PELO facilitates PLK1-induced the ubiquitination and degradation of Smad4 and promotes the progression of prostate cancer. Oncogene 2022; 41:2945-2957. [PMID: 35437307 DOI: 10.1038/s41388-022-02316-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 04/01/2022] [Accepted: 04/05/2022] [Indexed: 12/16/2022]
Abstract
PLK1 and Smad4 are two important factors in prostate cancer initiation and progression. They have been reported to play the opposite role in Pten-deleted mice, one is an oncogene, the other is a tumor suppressor. Moreover, they could reversely regulate the PI3K/AKT/mTOR pathway and the activation of MYC. However, the connections between PLK1 and Smad4 have never been studied. Here, we showed that PLK1 could interact with Smad4 and promote the ubiquitination and degradation of Smad4 in PCa cells. PLK1 and PELO could bind to different domains of Smad4 and formed a protein complex. PELO facilitated the degradation of Smad4 through cooperating with PLK1, thereby resulting in proliferation and metastasis of prostate cancer cell. Changes in protein levels of Smad4 led to the alteration of biological function that caused by PLK1 in prostate cancer cells. Further studies showed that PELO upregulation was positively associated with high grade PCa and knockdown of PELO expression significantly decreased PCa cell proliferation and metastasis in vitro and vivo. PELO knockdown in PCa cells could enhance the tumor suppressive role of PLK1 inhibitor. In addition, blocking the interaction between PELO and Smad4 by using specific peptide could effectively inhibit PCa cell metastasis ability in vitro and vivo. Overall, these findings identified a novel regulatory relationship among PLK1, Smad4 and PELO, and provided a potential therapeutic strategy for advanced PCa therapy by co-targeting PLK1 and PELO.
Collapse
Affiliation(s)
- Ping Gao
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
| | - Jing-Lan Hao
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Qian-Wen Xie
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Gui-Qin Han
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Bin-Bing Xu
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Hang Hu
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Na-Er Sa
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Xiao-Wen Du
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China
| | - Hai-Long Tang
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jian Yan
- School of Medicine, Northwest University, Xi'an, 710069, China.,Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Xiao-Ming Dong
- College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
| |
Collapse
|
|
28
|
S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions. Nat Commun 2022; 13:1548. [PMID: 35318320 PMCID: PMC8941131 DOI: 10.1038/s41467-022-28910-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022] Open
Abstract
Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers. The direct upstream regulation of PDK1 is not fully understood. Here the authors demonstrate that S6K1 directly phosphorylates PDK1 to inhibit AKT kinase activity and its ability to drive tumourigenesis.
Collapse
|
|
29
|
BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer. Proc Natl Acad Sci U S A 2022; 119:2109133119. [PMID: 35105803 PMCID: PMC8832982 DOI: 10.1073/pnas.2109133119] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.
Collapse
|
|
30
|
The Landscape of PDK1 in Breast Cancer. Cancers (Basel) 2022; 14:cancers14030811. [PMID: 35159078 PMCID: PMC8834120 DOI: 10.3390/cancers14030811] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 12/31/2021] [Indexed: 02/04/2023] Open
Abstract
Given that 3-phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in the malignant biological behaviors of a wide range of cancers, we review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and characterize the interaction networks of PDK1. Then, we establish the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More importantly, we sort the current preclinical or clinical trials of PDK1-targeted therapy in BC and find that, even though no selective PDK1 inhibitor is currently available for BC therapy, the combination trials of PDK1-targeted therapy and other agents have provided some benefit. Thus, there is increasing anticipation that PDK1-targeted therapy will have its space in future therapeutic approaches related to BC, and we hope the novel approaches of targeted therapy will be conducive to ameliorating the dismal prognosis of BC patients.
Collapse
|
|
31
|
Lier S, Sellmer A, Orben F, Heinzlmeir S, Krauß L, Schneeweis C, Hassan Z, Schneider C, Patricia Gloria Schäfer A, Pongratz H, Engleitner T, Öllinger R, Kuisl A, Bassermann F, Schlag C, Kong B, Dove S, Kuster B, Rad R, Reichert M, Wirth M, Saur D, Mahboobi S, Schneider G. A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer. Bioorg Chem 2022; 119:105505. [PMID: 34838332 DOI: 10.1016/j.bioorg.2021.105505] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 10/06/2021] [Accepted: 11/17/2021] [Indexed: 12/13/2022]
Abstract
Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.
Collapse
Affiliation(s)
- Svenja Lier
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Andreas Sellmer
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
| | - Felix Orben
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | | | - Lukas Krauß
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Christian Schneeweis
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Zonera Hassan
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Carolin Schneider
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | | | - Herwig Pongratz
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
| | - Thomas Engleitner
- Institute of Molecular Oncology and Functional Genomics, MRI, TU Munich, Germany
| | - Rupert Öllinger
- Institute of Molecular Oncology and Functional Genomics, MRI, TU Munich, Germany
| | - Anna Kuisl
- Medical Clinic and Policlinic III, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Florian Bassermann
- Medical Clinic and Policlinic III, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Christoph Schlag
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany
| | - Bo Kong
- Department of Surgery, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; Department of General Surgery, University of Ulm, 89081 Ulm, Germany
| | - Stefan Dove
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, TU Munich, 85354 Freising, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), TU Munich, 85354 Freising, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, MRI, TU Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Maximilian Reichert
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Center for Protein Assemblies (CPA), Technische Universität München, 85747 Garching, Germany
| | - Matthias Wirth
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Dieter Saur
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Institute for Translational Cancer Research and Experimental Cancer Therapy, Klinikum Rechts der Isar, TU Munich, Germany
| | - Siavosh Mahboobi
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
| | - Günter Schneider
- Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, 37075 Göttingen, Germany.
| |
Collapse
|
|
32
|
Tang Y, Chen Y, Zhang Z, Tang B, Zhou Z, Chen H. Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective. Pharmaceutics 2021; 13:pharmaceutics13122116. [PMID: 34959397 PMCID: PMC8708448 DOI: 10.3390/pharmaceutics13122116] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/19/2021] [Accepted: 12/02/2021] [Indexed: 02/05/2023] Open
Abstract
Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials.
Collapse
Affiliation(s)
- Yongquan Tang
- Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (Z.Z.)
| | - Yan Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (Z.Z.)
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (Z.Z.)
| | - Bo Tang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Zongguang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (Z.Z.)
- Correspondence: (Z.Z.); (H.C.)
| | - Haining Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (Z.Z.)
- Correspondence: (Z.Z.); (H.C.)
| |
Collapse
|
|
33
|
Yu Z, Deng P, Chen Y, Liu S, Chen J, Yang Z, Chen J, Fan X, Wang P, Cai Z, Wang Y, Hu P, Lin D, Xiao R, Zou Y, Huang Y, Yu Q, Lan P, Tan J, Wu X. Inhibition of the PLK1-Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100759. [PMID: 34881526 PMCID: PMC8655181 DOI: 10.1002/advs.202100759] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/29/2021] [Indexed: 06/13/2023]
Abstract
Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo-like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle-related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle-related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1-MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti-tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1-MYC-CDC7 axis in the treatment of oxaliplatin-based chemotherapy.
Collapse
Affiliation(s)
- Zhaoliang Yu
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Peng Deng
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Yufeng Chen
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Shini Liu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Jinghong Chen
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Zihuan Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesGuangdong Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Jianfeng Chen
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Xinjuan Fan
- Department of PathologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510060P. R. China
| | - Peili Wang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Zerong Cai
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Yali Wang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Peishan Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesGuangdong Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Dezheng Lin
- Department of Endoscopic SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510060P. R. China
| | - Rong Xiao
- Department of Biomedical SciencesCity University of Hong KongHong KongSAR999077China
| | - Yifeng Zou
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Yan Huang
- Department of PathologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510060P. R. China
| | - Qiang Yu
- Cancer and Stem Cell Biology ProgramDuke‐NUS Medical SchoolSingapore169857Singapore
- Genome Institute of SingaporeA*STARSingapore138672Singapore
| | - Ping Lan
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesGuangdong Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| | - Jing Tan
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdong510060P. R. China
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouGuangdong510095P. R. China
| | - Xiaojian Wu
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesGuangdong Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510655P. R. China
| |
Collapse
|
|
34
|
Liu R, Jiang Z, Kong W, Zheng S, Dai T, Wang G. A Novel Nine-Gene Signature Associated With Immune Infiltration for Predicting Prognosis in Hepatocellular Carcinoma. Front Genet 2021; 12:730732. [PMID: 34917126 PMCID: PMC8669621 DOI: 10.3389/fgene.2021.730732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 11/08/2021] [Indexed: 01/10/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its prognosis remains unsatisfactory. The identification of new and effective markers is helpful for better predicting the prognosis of patients with HCC and for conducting individualized management. The oncogene Aurora kinase A (AURKA) is involved in a variety of tumors; however, its role in liver cancer is poorly understood. The aim of this study was to establish AURKA-related gene signatures for predicting the prognosis of patients with HCC. Methods: We first analyzed the expression of AURKA in liver cancer and its prognostic significance in different data sets. Subsequently, we selected genes with prognostic value related to AURKA and constructed a gene signature based on them. The predictive ability of the gene signature was tested using the HCC cohort development and verification data sets. A nomogram was constructed by integrating the risk score and clinicopathological characteristics. Finally, the influence of the gene signature on the immune microenvironment in HCC was comprehensively analyzed. Results: We found that AURKA was highly expressed in HCC, and it exhibited prognostic value. We selected eight AURKA-related genes with prognostic value through the protein-protein interaction network and successfully constructed a gene signature. The nine-gene signature could effectively stratify the risk of patients with HCC and demonstrated a good ability in predicting survival. The nomogram showed good discrimination and consistency of risk scores. In addition, the high-risk group showed a higher percentage of immune cell infiltration (i.e., macrophages, myeloid dendritic cells, neutrophils, and CD4+T cells). Moreover, the immune checkpoints SIGLEC15, TIGIT, CD274, HAVCR2, and PDCD1LG2 were also higher in the high-risk group versus the low-risk group. Conclusions: This gene signature may be useful prognostic markers and therapeutic targets in patients with HCC.
Collapse
Affiliation(s)
- Rongqiang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - ZeKun Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weihao Kong
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shiyang Zheng
- Department of Breast Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Tianxing Dai
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guoying Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
35
|
Wu S, Shao M, Zhang Y, Shi D. Activation of RSK2 upregulates SOX8 to promote methotrexate resistance in gestational trophoblastic neoplasia. J Transl Med 2021; 101:1494-1504. [PMID: 34373588 DOI: 10.1038/s41374-021-00651-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 11/09/2022] Open
Abstract
Resistance to chemotherapy is frequently driven by aberrantly activated kinases in cancer. Herein, we characterized the global phosphoproteomic alterations associated with methotrexate (MTX) resistance in gestational trophoblastic neoplastic (GTN) cells. A total of 1111 phosphosites on 713 proteins were significantly changed, with highly elevated Ribosomal S6 Kinase 2 (RSK2) phosphorylation (pS227) observed in MTX-resistant GTN cells. Activation of RSK2 promoted cell proliferation and survival after MTX treatment in GTN cell models. Interestingly, RSK2 might play an important role in the regulation of reactive oxygen species (ROS) homeostasis, as manipulation of RSK2 activation affected ROS accumulation and SOX8 expression in GTN cells. In addition, overexpression of SOX8 partly rescued cell proliferation and survival in RSK2-depleted MTX-resistant GTN cells, suggesting that SOX8 might serve as a downstream effector of RSK2 to promote MTX resistance in GTN cells. Highly activated RSK2/SOX8 signaling was observed in MTX-resistant GTN specimens. Further, the RSK2 inhibitor BIX02565 effectively reduced SOX8 expression, induced ROS accumulation, and enhanced MTX-induced cytotoxicity in vitro and in vivo. Collectively, our findings suggested that RSK2 activation could promote MTX resistance via upregulating SOX8 and attenuating MTX-induced ROS in GTN cells, which may help to develop experimental therapeutics to treat MTX-resistant GTN.
Collapse
Affiliation(s)
- Shaobin Wu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mingjie Shao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yi Zhang
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China
| | - Dazun Shi
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
|
36
|
PDK1 Inhibitor BX795 Improves Cisplatin and Radio-Efficacy in Oral Squamous Cell Carcinoma by Downregulating the PDK1/CD47/Akt-Mediated Glycolysis Signaling Pathway. Int J Mol Sci 2021; 22:ijms222111492. [PMID: 34768921 PMCID: PMC8584253 DOI: 10.3390/ijms222111492] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Oral squamous cell carcinoma (OSCC) has a high prevalence and predicted global mortality rate of 67.1%, necessitating better therapeutic strategies. Moreover, the recurrence and resistance of OSCC after chemo/radioresistance remains a major bottleneck for its effective treatment. Molecular targeting is one of the new therapeutic approaches to target cancer. Among a plethora of targetable signaling molecules, PDK1 is currently rising as a potential target for cancer therapy. Its aberrant expression in many malignancies is observed associated with glycolytic re-programming and chemo/radioresistance. Methods: Furthermore, to better understand the role of PDK1 in OSCC, we analyzed tissue samples from 62 patients with OSCC for PDK1 expression. Combining in silico and in vitro analysis approaches, we determined the important association between PDK1/CD47/LDHA expression in OSCC. Next, we analyzed the effect of PDK1 expression and its connection with OSCC orosphere generation and maintenance, as well as the effect of the combination of the PDK1 inhibitor BX795, cisplatin and radiotherapy in targeting it. Results: Immunohistochemical analysis revealed that higher PDK1 expression is associated with a poor prognosis in OSCC. The immunoprecipitation assay indicated PDK1/CD47 binding. PDK1 ligation significantly impaired OSCC orosphere formation and downregulated Sox2, Oct4, and CD133 expression. The combination of BX795 and cisplatin markedly reduced in OSCC cell’s epithelial-mesenchymal transition, implying its synergistic effect. p-PDK1, CD47, Akt, PFKP, PDK3 and LDHA protein expression were significantly reduced, with the strongest inhibition in the combination group. Chemo/radiotherapy together with abrogation of PDK1 inhibits the oncogenic (Akt/CD47) and glycolytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming. Conclusions: Therefore, the results from our current study may serve as a basis for developing new therapeutic strategies against chemo/radioresistant OSCC.
Collapse
|
|
37
|
Liu S, Zou Q, Chen JP, Yao X, Guan P, Liang W, Deng P, Lai X, Yin J, Chen J, Chen R, Yu Z, Xiao R, Sun Y, Hong JH, Liu H, Lu H, Chen J, Bei JX, Koh J, Chan JY, Wang B, Kang T, Yu Q, Teh BT, Liu J, Xiong Y, Tan J. Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer. J Clin Invest 2021; 131:e145035. [PMID: 34464356 DOI: 10.1172/jci145035] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.
Collapse
Affiliation(s)
- Shini Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Qiong Zou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jie-Ping Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xiaosai Yao
- Institute of Molecular and Cell Biology, Singapore
| | - Peiyong Guan
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
| | - Weiting Liang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Peng Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xiaowei Lai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jiaxin Yin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jinghong Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Rui Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Zhaoliang Yu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rong Xiao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Yichen Sun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jing Han Hong
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
| | - Hui Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Huaiwu Lu
- Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianfeng Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jin-Xin Bei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Joanna Koh
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Jason Yongsheng Chan
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Baohua Wang
- The First Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Tiebang Kang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Qiang Yu
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.,Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Bin-Tean Teh
- Institute of Molecular and Cell Biology, Singapore.,Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.,Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore.,SingHealth Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore
| | - Jihong Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Ying Xiong
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jing Tan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.,Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
38
|
Carroll PA, Freie BW, Cheng PF, Kasinathan S, Gu H, Hedrich T, Dowdle JA, Venkataramani V, Ramani V, Wu X, Raftery D, Shendure J, Ayer DE, Muller CH, Eisenman RN. The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis. PLoS Biol 2021; 19:e3001085. [PMID: 34669700 PMCID: PMC8528285 DOI: 10.1371/journal.pbio.3001085] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 09/24/2021] [Indexed: 01/02/2023] Open
Abstract
Male germ cell (GC) production is a metabolically driven and apoptosis-prone process. Here, we show that the glucose-sensing transcription factor (TF) MAX-Like protein X (MLX) and its binding partner MondoA are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and GC apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific GC transcripts and proteins. Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, obligate components of male-specific GC development, and apoptotic effectors. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors (MGCTs).
Collapse
Affiliation(s)
- Patrick A. Carroll
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian W. Freie
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Pei Feng Cheng
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Sivakanthan Kasinathan
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Haiwei Gu
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America
| | - Theresa Hedrich
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - James A. Dowdle
- Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Vivek Venkataramani
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Vijay Ramani
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Xiaoying Wu
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Daniel Raftery
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America
| | - Jay Shendure
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
- Howard Hughes Medical Institute, Seattle, Washington, United States of America
- Brotman Baty Institute for Precision Medicine, Seattle, Washington, United States of America
| | - Donald E. Ayer
- Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America
| | - Charles H. Muller
- Male Fertility Lab, Department of Urology, University of Washington, Seattle, Washington, United States of America
| | - Robert N. Eisenman
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| |
Collapse
|
|
39
|
Xie Y, Zhang W, Guo L, Kril LM, Begley KL, Sviripa VM, Chen X, Liu X, Lee EY, He D, Wang C, Gao T, Liu X, Evers BM, Watt DS, Liu C. Potent Synergistic Effect on C-Myc-Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor. Mol Cancer Ther 2021; 20:1893-1903. [PMID: 34376582 PMCID: PMC8492540 DOI: 10.1158/1535-7163.mct-20-1017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/24/2021] [Accepted: 07/23/2021] [Indexed: 11/16/2022]
Abstract
Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as N7,N7 -dimethyl-3-(1-methyl-1H-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent in vitro inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy-homeostasis master regulator. We explored the effect of ISQs on cell metabolism. Seahorse assays measuring oxygen consumption rate (OCR) indicated that ISQ-1 inhibited complex I (i.e., NADH ubiquinone oxidoreductase) in the mitochondrial, electron transport chain (ETC). In addition, ISQ-1 treatment showed remarkable synergistic depletion of oncogenic c-Myc protein level in vitro and induced strong tumor remission in vivo when administered together with BI2536, a polo-like kinase-1 (Plk1) inhibitor. These studies point toward the potential value of dual drug therapies targeting the ETC and Plk-1 for the treatment of c-Myc-driven cancers.
Collapse
Affiliation(s)
- Yanqi Xie
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Wen Zhang
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Lichao Guo
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Center for Drug Innovation and Discovery, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Liliia M Kril
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky
| | - Kristin L Begley
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky
| | - Vitaliy M Sviripa
- Center for Drug Innovation and Discovery, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
- Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky
| | - Xi Chen
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Center for Drug Innovation and Discovery, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Xifu Liu
- Center for Drug Innovation and Discovery, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Eun Y Lee
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Pathology & Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Daheng He
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Chi Wang
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Tianyan Gao
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Xiaoqi Liu
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - B Mark Evers
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Surgery, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - David S Watt
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky.
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky
| | - Chunming Liu
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky.
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| |
Collapse
|
|
40
|
Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia. Oncogene 2021; 40:6166-6179. [PMID: 34535769 PMCID: PMC8556320 DOI: 10.1038/s41388-021-02012-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 08/25/2021] [Accepted: 09/07/2021] [Indexed: 12/22/2022]
Abstract
The transcription factors PAX5, IKZF1, and EBF1 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrate that compound heterozygous loss of multiple genes critical for B and T cell development drives transformation, including Pax5+/-xEbf1+/-, Pax5+/-xIkzf1+/-, and Ebf1+/-xIkzf1+/- mice for B-ALL, or Tcf7+/-xIkzf1+/- mice for T-ALL. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we performed a Sleeping Beauty (SB) transposon screen that identified cooperating partners including gain-of-function mutations in Stat5b (~65%) and Jak1 (~68%), or loss-of-function mutations in Cblb (61%) and Myb (32%). These findings underscore the role of JAK/STAT5B signaling in B cell transformation and demonstrate roles for loss-of-function mutations in Cblb and Myb in transformation. RNA-Seq studies demonstrated upregulation of a PDK1>SGK3>MYC pathway; treatment of Pax5+/-xEbf1+/- leukemia cells with PDK1 inhibitors blocked proliferation in vitro. In addition, we identified a conserved transcriptional gene signature between human and murine leukemias characterized by upregulation of myeloid genes, most notably involving the GM-CSF pathway, that resemble a B cell/myeloid mixed-lineage leukemia. Thus, our findings identify multiple mechanisms that cooperate with defects in B cell transcription factors to generate either progenitor B cell or mixed B/myeloid-like leukemias.
Collapse
|
|
41
|
Dual Targeting of EGFR with PLK1 Exerts Therapeutic Synergism in Taxane-Resistant Lung Adenocarcinoma by Suppressing ABC Transporters. Cancers (Basel) 2021; 13:cancers13174413. [PMID: 34503223 PMCID: PMC8430738 DOI: 10.3390/cancers13174413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/29/2021] [Accepted: 08/05/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Our previous studies led us to hypothesize that downregulation of PLK1 expression or its activity can overcome the hurdles of taxane resistance by downregulating ABC transporters. Targeting PLK1 with shRNA or non-functional mutants downregulated ABCB1, ABCC9, and ABCG2 in paclitaxel-resistant lung adenocarcinoma (LUADTXR), similar to the downregulation effects from treatment with PLK1 inhibitors. Since EGFR is highly expressed in LUADTXR cells, gefitinib was combined with PLK1 inhibitors. Under these conditions, LUADTXR cells tend to undergo apoptosis more effectively than parental cells, showing a synergistic effect on downregulation of ABC transporters through c-Myc or AP-1. Clinical data provide evidence for the relationship between survival rates and expressions of PLK1 and EGFR in LUAD patients. Taken together, our data suggest that a combination of gefitinib and PLK1 inhibitors exerts strong synergism in LUADTXR, providing a benefit to overcome the limitations associated with taxanes. Abstract To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation of ABC transporters. To explore this, various versions of PLK1 including a constitutively active version, kinase-dead form, and polo-box domain mutant were expressed in paclitaxel-resistant lung adenocarcinoma (LUADTXR). Targeting PLK1 using shRNA or non-functional mutants downregulated ABCB1, ABCC9, and ABCG2 in LUADTXR cells, which was similar to the downregulation effects from treatment with PLK1 inhibitors. The high expression of EGFR in LUAD led us to administer gefitinib, showing a markedly reduced EGFR level in LUADTXR cells. When gefitinib and PLK1 inhibitors were combined, LUADTXR cells tended to undergo apoptosis more effectively than parental cells, showing a synergistic effect on the downregulation of ABC transporters through c-Myc and AP-1. Clinical data provide evidence for the relevance between survival rates and expressions of PLK1 and EGFR in LUAD patients. Based on these results, we suggest that a combination of gefitinib and PLK1 inhibitors exerts strong synergism in LUADTXR, which helps to overcome the limitations associated with taxanes.
Collapse
|
|
42
|
Wang B, Huang X, Liang H, Yang H, Guo Z, Ai M, Zhang J, Khan M, Tian Y, Sun Q, Mao Z, Zheng R, Yuan Y. PLK1 Inhibition Sensitizes Breast Cancer Cells to Radiation via Suppressing Autophagy. Int J Radiat Oncol Biol Phys 2021; 110:1234-1247. [PMID: 33621661 DOI: 10.1016/j.ijrobp.2021.02.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/13/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Polo-like kinase 1 (PLK1) is a protein kinase that is overexpressed in breast cancer and may represent an attractive target for breast cancer treatment. However, few studies have investigated the relationship between PLK1 and radiosensitivity in breast cancer. Here, we attempted to explore whether PLK1 inhibition could sensitize breast cancer cells to radiation. METHODS AND MATERIALS Breast cancer cells were treated with PLK1 small interference RNA or the PLK1-inhibitor, GSK461364. Cell proliferation was assessed using a colony formation assay. Cell cycle analyses were performed by flow cytometry. DNA damage, autophagy, and reactive oxygen species induced by ionizing radiation were detected by immunofluorescence, Western blot, and flow cytometry, respectively. Microtubule-associated protein 1 light chain 3 alpha (LC3) puncta were detected using an immunofluorescence assay. A clonogenic survival assay was used to determine the effect of PLK1 inhibition on cell radiosensitivity. A xenograft mouse model of breast cancer cells was used to investigate the potential synergistic effects of PLK1 inhibition and irradiation in vivo. Finally, the expression of PLK1 and LC3 in the breast cancer tissues was evaluated by immunohistochemistry. RESULTS PLK1 inhibition significantly suppressed the proliferation and increased the radiosensitivity of breast cancer cells. Pharmacologic inhibition of PLK1 by the selective inhibitor, GSK461364, enhanced the radiosensitivity of breast cancer cells in vivo (n = 4, P = .002). Mechanistically, PLK1 inhibition led to the downregulation of radiation-induced reactive oxygen species and autophagy, thereby increasing the radiosensitivity of breast cancer cells. Additionally, we detected a positive correlation between the expression of PLK1 and LC3 in human breast cancer samples (n = 102, R = 0.486, P = .005). CONCLUSIONS Our findings indicate that PLK1 inhibition enhances the radiosensitivity of breast cancer cells in a manner associated with the suppression of radiation-induced autophagy. The inhibition of PLK1 represents a promising strategy for radiosensitizing breast cancer.
Collapse
Affiliation(s)
- Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Huiping Liang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Hongli Yang
- Department of Radiation Oncology, Shenzhen People's Hospital, Shenzhen, Guangdong Province, People's Republic of China
| | - Zhaoze Guo
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Meiling Ai
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Muhammad Khan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Quanquan Sun
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zixu Mao
- Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, Georgia
| | - Ronghui Zheng
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China.
| |
Collapse
|
|
43
|
Yang H, Xie S, Liang B, Tang Q, Liu H, Wang D, Huang G. Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil. J Cancer 2021; 12:4862-4872. [PMID: 34234856 PMCID: PMC8247374 DOI: 10.7150/jca.58846] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/30/2021] [Indexed: 11/05/2022] Open
Abstract
Chemoresistance challenges the clinical treatment of colorectal cancer and requires an urgent solution. Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in glucose metabolism that mediates the malignant transformation of tumors. However, the mechanisms by which IDH1 is involved in colorectal cancer cell proliferation and drug resistance induction remain unclear. In this study, we found that IDH1 was highly expressed in human colorectal cancer tissues and could be used to indicate a high-grade tumor. In vitro gene overexpression and knockdown were used to determine whether IDH1 promoted the proliferation of the colorectal cancer cell line HCT8 and resistance to 5-Fluorouracil (5FU). Further studies have shown that the 5FU-resistant cell line, HCT8FU, secreted exosomes that contained a high level of IDH1 protein. The exosomal IDH1 derived from 5FU-resistant cells enhanced the resistance of 5FU-sensitive cells. Metabolic assays revealed that exosomes derived from 5FU-resistant cells promoted a decrease in the level of IDH1-mediated NADPH, which is associated with the development of 5FU resistance in colorectal cancer cells. Therefore, exosomal IDH1 may be the transmitter and driver of chemoresistance in colorectal cancer and a potential chemotherapy target.
Collapse
Affiliation(s)
- Hao Yang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.,Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Sha Xie
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Beibei Liang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Qiqi Tang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Huanchen Liu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Dongliang Wang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.,Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.,Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| |
Collapse
|
|
44
|
Sun H, Wang C, Hu B, Gao X, Zou T, Luo Q, Chen M, Fu Y, Sheng Y, Zhang K, Zheng Y, Ren X, Yan S, Geng Y, Yang L, Dong Q, Qin L. Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3. Signal Transduct Target Ther 2021; 6:187. [PMID: 34035222 PMCID: PMC8149717 DOI: 10.1038/s41392-021-00579-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 03/08/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Intercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.
Collapse
Affiliation(s)
- Haoting Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Chaoqun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Beiyuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Xiaomei Gao
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Tiantian Zou
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qin Luo
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Mo Chen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yuanyuan Sheng
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Kaili Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yan Zheng
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xudong Ren
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Shican Yan
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yan Geng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Luyu Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| |
Collapse
|
|
45
|
Epigenetic-Based Therapy-A Prospective Chance for Medulloblastoma Patients' Recovery. Int J Mol Sci 2021; 22:ijms22094925. [PMID: 34066495 PMCID: PMC8124462 DOI: 10.3390/ijms22094925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/25/2022] Open
Abstract
Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient's age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system's function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate.
Collapse
|
|
46
|
Domrachev B, Singh S, Li D, Rudloff U. Mini-Review: PDPK1 (3-phosphoinositide dependent protein kinase-1), An Emerging Cancer Stem Cell Target. ACTA ACUST UNITED AC 2021; 5:30-35. [PMID: 34079928 PMCID: PMC8168947 DOI: 10.29245/2578-2967/2021/1.1194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are subpopulations of tumor cells that possess abilities for self-renewal, differentiation, and tumor initiation. These rare but therapy-recalcitrant cells are assumed to repopulate tumors following administration of systemic chemotherapy driving therapy failure, tumor recurrence, and disease progression. In early clinical trials, anti-CSC therapies have found limited success to-date possibly due to the inherent heterogeneity and plasticity of CSCs and the incomplete characterization of essential CSC targets. Here, we review the role of 3-phosphoinositide dependent protein kinase-1 (PDPK1) as an emerging CSC target. While most previous studies have relied on CSC models which are based on lineage and tissue-specific marker profiles to define the relationships between putative target and CSC traits, this review discusses PDPK1 and its role in CSC biology with an emphasis on CSC systems which are based on proposed function like label-retaining cancer cells (LRCCs).
Collapse
Affiliation(s)
- Bogdan Domrachev
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Sitanshu Singh
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Dandan Li
- Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Udo Rudloff
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.,Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
|
47
|
Ocklenburg T, Neumann F, Wolf A, Vogel J, Göpelt K, Baumann M, Baumann J, Kranz P, Metzen E, Brockmeier U. In oxygen-deprived tumor cells ERp57 provides radioprotection and ensures proliferation via c-Myc, PLK1 and the AKT pathway. Sci Rep 2021; 11:7199. [PMID: 33785835 PMCID: PMC8009878 DOI: 10.1038/s41598-021-86658-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 03/17/2021] [Indexed: 01/07/2023] Open
Abstract
The disulfide isomerase ERp57, originally found in the endoplasmic reticulum, is located in multiple cellular compartments, participates in diverse cell functions and interacts with a huge network of binding partners. It was recently suggested as an attractive new target for cancer therapy due to its critical role in tumor cell proliferation. Since a major bottleneck in cancer treatment is the occurrence of hypoxic areas in solid tumors, the role of ERp57 in cell growth was tested under oxygen depletion in the colorectal cancer cell line HCT116. We observed a severe growth inhibition when ERp57 was knocked down in hypoxia (1% O2) as a consequence of downregulated c-Myc, PLK1, PDPK1 (PDK1) and AKT (PKB). Further, irradiation experiments revealed also a radiosensitizing effect of ERp57 depletion under oxygen deprivation. Compared to ERp57, we do not favour PDPK1 as a suitable pharmaceutical target as its efficient knockdown/chemical inhibition did not show an inhibitory effect on proliferation.
Collapse
Affiliation(s)
- Tobias Ocklenburg
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Fabian Neumann
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Alexandra Wolf
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Julia Vogel
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Kirsten Göpelt
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Melanie Baumann
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Jennifer Baumann
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Philip Kranz
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Eric Metzen
- Institut Für Physiologie, Universität Duisburg-Essen, Duisburg, Germany
| | - Ulf Brockmeier
- Department of Neurology, University Hospital Essen, Essen, Germany.
| |
Collapse
|
|
48
|
Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells. Cell Death Dis 2021; 12:85. [PMID: 33446653 PMCID: PMC7809409 DOI: 10.1038/s41419-020-03370-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/13/2020] [Accepted: 12/18/2020] [Indexed: 12/24/2022]
Abstract
Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.
Collapse
|
|
49
|
López-Cánovas JL, Del Rio-Moreno M, García-Fernandez H, Jiménez-Vacas JM, Moreno-Montilla MT, Sánchez-Frias ME, Amado V, L-López F, Fondevila MF, Ciria R, Gómez-Luque I, Briceño J, Nogueiras R, de la Mata M, Castaño JP, Rodriguez-Perálvarez M, Luque RM, Gahete MD. Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma. Cancer Lett 2021; 496:72-83. [PMID: 33038489 DOI: 10.1016/j.canlet.2020.10.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022]
Abstract
Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.
Collapse
Affiliation(s)
- Juan L López-Cánovas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Mercedes Del Rio-Moreno
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Helena García-Fernandez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Juan M Jiménez-Vacas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - M Trinidad Moreno-Montilla
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marina E Sánchez-Frias
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Víctor Amado
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Fernando L-López
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marcos F Fondevila
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Irene Gómez-Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Javier Briceño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Rubén Nogueiras
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Manuel de la Mata
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Justo P Castaño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel Rodriguez-Perálvarez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
| |
Collapse
|
|
50
|
Wang H, Tao Z, Feng M, Li X, Deng Z, Zhao G, Yin H, Pan T, Chen G, Feng Z, Li Y, Zhou Y. Dual PLK1 and STAT3 inhibition promotes glioblastoma cells apoptosis through MYC. Biochem Biophys Res Commun 2020; 533:368-375. [PMID: 32962858 DOI: 10.1016/j.bbrc.2020.09.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 09/05/2020] [Indexed: 12/27/2022]
Abstract
Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.
Collapse
Affiliation(s)
- Hao Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhennan Tao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ming Feng
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xuetao Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhitong Deng
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guozheng Zhao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Haoran Yin
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tingzheng Pan
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guangliang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zibin Feng
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yanyan Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Youxin Zhou
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| |
Collapse
|