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Xiong J, Deng C, Fu Y, Tang J, Xie J, Chen Y. Prognostic and Potential Therapeutic Roles of PRKDC Expression in Lung Cancer. Mol Biotechnol 2025; 67:2455-2466. [PMID: 39044064 DOI: 10.1007/s12033-024-01209-3] [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: 11/27/2023] [Accepted: 05/06/2024] [Indexed: 07/25/2024]
Abstract
PRKDC is a key factor involved in the ligation step of the non-homologous end joining pathway. Its dysfunction has proven to be a biomarker for radiosensitivity of cancer cells. However, the prognostic value of PRKDC and its underlying mechanisms have not been clarified yet. In this study, we found that PRKDC overexpressed in lung adenocarcinoma (LUAD) and is significantly related to unfavorable survival, while downregulation of PRKDC is link to inflamed tumor immune signature. Our further in vitro results also showed a potent antitumor efficacy of PRKDC inhibitors alone or combined with cisplatin in human lung cancer cells. This study demonstrated that PRKDC is a potential prognostic biomarker, immunotherapy target, and promising combination candidate for chemotherapy for lung cancer, and highlighted the potential of PRKDC-targeted inhibitors for the treatment of lung cancer.
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Affiliation(s)
- Jiani Xiong
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
- Cancer Bio-immunotherapy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Cuimin Deng
- Department of Pharmacy, QuanZhou Women's and Children's Hospital, Quanzhou, Fujian Province, People's Republic of China
| | - YunRong Fu
- Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Jingji Tang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
- Cancer Bio-immunotherapy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Jieming Xie
- Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China.
| | - Yu Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China.
- Cancer Bio-immunotherapy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China.
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2
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Meng X, Li X, Gao Y, Zhang S. Nuclear receptors as novel regulators that modulate cancer radiosensitivity and normal tissue radiotoxicity. Mol Cancer 2025; 24:155. [PMID: 40442680 PMCID: PMC12124050 DOI: 10.1186/s12943-025-02362-2] [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: 04/15/2025] [Accepted: 05/20/2025] [Indexed: 06/02/2025] Open
Abstract
Nuclear receptors (NRs) are a superfamily of transcription factors that are involved in various pathophysiological processes. The human genome contains 48 types of nuclear receptors, including steroid hormone receptors (e.g., estrogen receptor [ER] and vitamin D receptor [VDR]), nonsteroid hormone receptors (e.g. peroxisome proliferator-activated receptor [PPAR] and retinoic acid receptor [RAR]), and orphan nuclear receptors (e.g. neuron-derived clone 77 [Nur77] and testicular nuclear receptor 4 [TR4]) and certain nuclear receptors are specifically overexpressed in tumor cells or surrounding normal tissues. Radiotherapy is one of the main methods of tumor treatment, but radioresistance in tumors and radiotoxicity to normal tissues strongly affect radiotherapy efficacy. Accumulating evidence has indicated the critical role of nuclear receptor modulators (including agonists and antagonists) as promising radiosensitizers in radiotherapy through various mechanisms. In addition, several nuclear receptors and their agonists alleviate normal tissue toxicity during radiotherapy. Thus, nuclear receptors serve as novel targets for tumor radiosensitization and for protecting of normal tissues from radiation damage. This review summarizes the research progress of nuclear receptors and highlights a promising synergistic strategy in radiotherapy.
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Affiliation(s)
- Xiaochen Meng
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xiaoqian Li
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Yi Gao
- Department of Gastroenterology, Affiliated Jiangyin Hospital of Nantong University, Jiangyin, 214400, China.
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital), Mianyang, 621099, China.
- Medical College of Tibet University, Lasa, 850000, China.
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3
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Nesic K, Parker P, Swisher EM, Krais JJ. DNA repair and the contribution to chemotherapy resistance. Genome Med 2025; 17:62. [PMID: 40420317 PMCID: PMC12107761 DOI: 10.1186/s13073-025-01488-8] [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: 07/17/2024] [Accepted: 05/14/2025] [Indexed: 05/28/2025] Open
Abstract
The DNA damage response comprises a set of imperfect pathways that maintain cell survival following exposure to DNA damaging agents. Cancers frequently exhibit DNA repair pathway alterations that contribute to their intrinsic genome instability. This, in part, facilitates a therapeutic window for many chemotherapeutic agents whose mechanisms of action often converge at the generation of a double-strand DNA break. The development of therapy resistance occurs through countless molecular mechanisms that promote tolerance to DNA damage, often by preventing break formation or increasing repair capacity. This review broadly discusses the DNA damaging mechanisms of action for different classes of chemotherapeutics, how avoidance and repair of double-strand breaks can promote resistance, and strategic directions for counteracting therapy resistance.
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Affiliation(s)
- Ksenija Nesic
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Phoebe Parker
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | | | - John J Krais
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Yap TA, LoRusso P, Miller RE, Kristeleit R, Paulovich AG, McMorn S, Oplustil O'Connor L, Lombardi B, Marco-Casanova P, Gangl ET, Patel B, O'Connor MJ, Dean E, Zviezdin R, Plummer R. The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study. Br J Cancer 2025:10.1038/s41416-025-03053-x. [PMID: 40382524 DOI: 10.1038/s41416-025-03053-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/15/2025] [Accepted: 05/01/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Upregulation of DNA-dependent protein kinase (DNA-PK) is associated with poor prognosis and decreased response to DNA-damaging agents across cancer types. A Phase I/IIa study (NCT03907969) investigated the highly potent, selective DNA-PK inhibitor AZD7648 as monotherapy or combined with pegylated liposomal doxorubicin (PLD) in patients with advanced cancer. METHODS Thirty patients received escalating doses of AZD7648 as monotherapy (n = 14), starting at 5 mg QD, or with PLD 40 mg/m2 (n = 16). The primary objective was safety and tolerability. RESULTS AZD7648 monotherapy was administered at 5-160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1-7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response. DISCUSSION Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.
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Affiliation(s)
- Timothy A Yap
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | - Rowan E Miller
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Rebecca Kristeleit
- Department of Oncology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | | | | | | | | | | | - Eric T Gangl
- Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | | | | | - Emma Dean
- Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Ruth Plummer
- Newcastle University and Northern Centre for Cancer Care, Newcastle Hospitals NHS Trust, Newcastle Upon Tyne, UK
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Kovina AP, Luzhin AV, Tatarskiy VV, Deriglazov DA, Petrova NV, Petrova NV, Kondratyeva LG, Kantidze OL, Razin SV, Velichko AK. Disruption of RNA Splicing Increases Vulnerability of Cells to DNA-PK Inhibitors. Int J Mol Sci 2024; 25:11810. [PMID: 39519361 PMCID: PMC11546466 DOI: 10.3390/ijms252111810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
DNA-dependent protein kinase (DNA-PK) is a key effector of non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair. Since its identification, a substantial body of evidence has demonstrated that DNA-PK is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis in cancer patients. Recent studies have also uncovered novel functions of DNA-PK, shifting the paradigm of the role of DNA-PK in oncogenesis and renewing interest in targeting DNA-PK for cancer therapy. To gain genetic insight into the cellular pathways requiring DNA-PK activity, we used a CRISPR/Cas9 screen to identify genes in which defects cause hypersensitivity to DNA-PK inhibitors. We identified over one hundred genes involved in DNA replication, cell cycle regulation, and RNA processing that promoted cell survival when DNA-PK kinase activity was suppressed. This gene set will be useful for characterizing novel biological processes that require DNA-PK activity and identifying predictive biomarkers of response to DNA-PK inhibition in the clinic. We also validated several genes from this set and reported previously undescribed genes that modulate the response to DNA-PK inhibitors. In particular, we found that compromising the mRNA splicing pathway led to marked hypersensitivity to DNA-PK inhibition, providing a possible rationale for the combined use of splicing inhibitors and DNA-PK inhibitors for cancer therapy.
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Affiliation(s)
- Anastasia P. Kovina
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
| | - Artem V. Luzhin
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology RAS, 119334 Moscow, Russia;
| | - Victor V. Tatarskiy
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology RAS, 119334 Moscow, Russia;
- Institute of Gene Biology RAS, 119334 Moscow, Russia
| | - Dmitry A. Deriglazov
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
| | - Natalia V. Petrova
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
| | - Nadezhda V. Petrova
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
| | - Liya G. Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia;
| | - Omar L. Kantidze
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
| | - Sergey V. Razin
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
- Biological Faculty, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Artem K. Velichko
- Department of Cellular Genomics, Institute of Gene Biology RAS, 119334 Moscow, Russia; (A.P.K.); (A.V.L.); (D.A.D.); (N.V.P.); (N.V.P.); (O.L.K.); (S.V.R.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology RAS, 119334 Moscow, Russia;
- Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
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Du J, Chen F, Chen Z, Zhao W, Wang J, Zhou M. LncRNA LINC01664 promotes cancer resistance through facilitating homologous recombination-mediated DNA repair. DNA Repair (Amst) 2024; 143:103770. [PMID: 39357141 DOI: 10.1016/j.dnarep.2024.103770] [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: 05/26/2024] [Revised: 09/14/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
The intracellular responses to DNA double-strand breaks (DSB) repair are crucial for genomic stability and play an essential role in cancer resistance. In addition to canonical DSB repair proteins, long non-coding RNAs (lncRNAs) have been found to be involved in this sophisticated network. In the present study, we performed a loss-of-function screen for a customized siRNA Premix Library to identify lncRNAs that participate in homologous recombination (HR) process. Among the candidates, we identified LINC01664 as a novel lncRNA required for HR repair. Furthermore, LINC01664 knockdown significantly increased the sensitivity of cancer cells to DNA damage agents such as ionizing radiation and genotoxic drugs. Mechanistically, LINC01664 interacted with Sirt1 promoter and then activated Sirt1 transcription, which contributed to HR-mediated DNA damage repair. In summary, our findings revealed a new mechanism of LINC01664 in DNA damage repair, providing evidence for a potential therapeutic strategy for eliminating the treatment bottlenecks caused by cancer resistance to chemotherapy and radiotherapy.
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Affiliation(s)
- Jie Du
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China; Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
| | - Fuqiang Chen
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zihan Chen
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Wenna Zhao
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jianyu Wang
- Key Laboratory of Occupational Environment and Health, Guangzhou Twelfth People's Hospital, Guangzhou, China
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
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7
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Liu Y, Niu M, Luo Y, Pan M, Hong S. DNA damage response and inflammatory response: Two traffic lights for HPVs on the road to transformation. J Med Virol 2024; 96:e29815. [PMID: 39073137 DOI: 10.1002/jmv.29815] [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: 01/05/2024] [Revised: 06/17/2024] [Accepted: 07/08/2024] [Indexed: 07/30/2024]
Abstract
Human papillomaviruses (HPVs) are non-enveloped double-stranded DNA viruses. When HPV infection persists, infected tissues can develop many HPV-related diseases such as cervical cancer and head and neck squamous cell carcinoma. To establish their persistent infection, HPVs have evolved mechanisms to manipulate the host cellular processes such as DNA damage response (DDR), which includes homologous recombination, nonhomologous end joining, and microhomology-mediated end joining. Additionally, HPVs utilize host inflammatory processes to facilitate their life cycles. Here, we bridge the concepts of DDR and inflammatory response, and discuss how HPV proteins orchestrate a sophisticated manipulation of DDR and inflammation to promote their viral replication, ultimately fostering the progression of infected cells towards oncogenic transformation to malignancy.
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Affiliation(s)
- Yanfei Liu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Mengda Niu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Ying Luo
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Min Pan
- Department of Otorhinolaryngology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shiyuan Hong
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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8
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Chen X, Chen C, Luo C, Liu J, Lin Z. Discovery of UMI-77 as a novel Ku70/80 inhibitor sensitizing cancer cells to DNA damaging agents in vitro and in vivo. Eur J Pharmacol 2024; 975:176647. [PMID: 38754534 DOI: 10.1016/j.ejphar.2024.176647] [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: 12/15/2023] [Revised: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 05/18/2024]
Abstract
The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC50 value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.
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Affiliation(s)
- Xuening Chen
- College of Chemistry, Fuzhou University, Fuzhou, 350108, China
| | - Changkun Chen
- College of Chemistry, Fuzhou University, Fuzhou, 350108, China
| | - Chengmiao Luo
- College of Chemistry, Fuzhou University, Fuzhou, 350108, China
| | - Jianyong Liu
- College of Chemistry, Fuzhou University, Fuzhou, 350108, China
| | - Zhonghui Lin
- College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
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9
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Chakrabarti D, Qayoom S, Srivastava K, Resu AV, Kukreja D, Goel MM, Singh US, Akhtar N, Rajan S, Verma M, Gupta R, Bhatt MLB. Cancer stem cell biomarkers SOX2 and Oct4 in cervical cancer patients undergoing chemoradiotherapy. Asia Pac J Clin Oncol 2024; 20:407-415. [PMID: 38403883 DOI: 10.1111/ajco.14049] [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: 09/29/2022] [Revised: 01/21/2024] [Accepted: 02/02/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND Cancer stem cell biomarkers SRY (sex-determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (Oct4) account for radioresistance in cervical squamous cell cancers (CSCCs). Their clinical implications are limited and contradictory. METHODS In this prospective cohort study, we recruited patients with FIGO IB2-IVA CSCC treated with primary chemoradiotherapy on regular follow-up. Tissue biopsy specimens were evaluated for SOX2 and Oct4 expression by immunohistochemistry, quantified by a product of proportion and intensity scores. RESULTS A total of 59 patients were included. Most had a moderately differentiated (81%), keratinizing (59%) CSCC, and ≥FIGO stage IIB disease (95%). SOX2 expression (high:low 21:38 patients) and Oct4 expression (high:low 4:55 patients) had a significant interrelation (p = 0.005, odds ratio (95% CI) - 1.23 (1.004-1.520)). At a median follow-up of 36 months, the 3-year overall survival (OS) was 60% and 53% for low and high SOX2 expression (p = 0.856), and 54% and 100% for low and high Oct4 expression (p = 0.114). The 3-year disease-frese survival (DFS) was 65% and 50% in the low and high SOX2 expression (p = 0.259), and 59% and 75% for low and high Oct4 expression (p = 0.598). SOX2 expression was the only variable significantly associated with a lower OS and DFS on regression analysis. CONCLUSION Our study demonstrated a trend toward improved OS and DFS with low SOX2 and high Oct4 expression in CSCC patients undergoing chemoradiotherapy.
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Affiliation(s)
- Deep Chakrabarti
- Department of Radiotherapy, King George's Medical University, Lucknow, India
- The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Sumaira Qayoom
- Department of Pathology, King George's Medical University, Lucknow, India
| | - Kirti Srivastava
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Abigail Veravolu Resu
- Department of Radiotherapy, King George's Medical University, Lucknow, India
- Department of Radiation Oncology, Super Speciality Cancer Institute & Hospital, Lucknow, India
| | - Divya Kukreja
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Madhu Mati Goel
- Department of Pathology, King George's Medical University, Lucknow, India
- Laboratory Medicine, Medanta Hospital, Lucknow, India
| | - U S Singh
- Department of Pathology, King George's Medical University, Lucknow, India
| | - Naseem Akhtar
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Shiv Rajan
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Mranalini Verma
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Rajeev Gupta
- Department of Radiotherapy, King George's Medical University, Lucknow, India
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10
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Ng YB, Akincilar SC. Shaping DNA damage responses: Therapeutic potential of targeting telomeric proteins and DNA repair factors in cancer. Curr Opin Pharmacol 2024; 76:102460. [PMID: 38776747 DOI: 10.1016/j.coph.2024.102460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 10/06/2023] [Accepted: 10/11/2023] [Indexed: 05/25/2024]
Abstract
Shelterin proteins regulate genomic stability by preventing inappropriate DNA damage responses (DDRs) at telomeres. Unprotected telomeres lead to persistent DDR causing cell cycle inhibition, growth arrest, and apoptosis. Cancer cells rely on DDR to protect themselves from DNA lesions and exogenous DNA-damaging agents such as chemotherapy and radiotherapy. Therefore, targeting DDR machinery is a promising strategy to increase the sensitivity of cancer cells to existing cancer therapies. However, the success of these DDR inhibitors depends on other mutations, and over time, patients develop resistance to these therapies. This suggests the need for alternative approaches. One promising strategy is co-inhibiting shelterin proteins with DDR molecules, which would offset cellular fitness in DNA repair in a mutation-independent manner. This review highlights the associations and dependencies of the shelterin complex with the DDR proteins and discusses potential co-inhibition strategies that might improve the therapeutic potential of current inhibitors.
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Affiliation(s)
- Yu Bin Ng
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Semih Can Akincilar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
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11
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Mishra SV, Banerjee A, Sarkar D, Thangarathnam V, Bagal B, Hasan SK, Dutt S. DNA-PKcs-mediated transcriptional regulation of TOP2B drives chemoresistance in acute myeloid leukemia. J Cell Sci 2024; 137:jcs261931. [PMID: 38240344 DOI: 10.1242/jcs.261931] [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: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 02/15/2024] Open
Abstract
Anthracyclines, topoisomerase II enzyme poisons that cause DNA damage, are the mainstay of acute myeloid leukemia (AML) treatment. However, acquired resistance to anthracyclines leads to relapse, which currently lacks effective treatment and is the cause of poor survival in individuals with AML. Therefore, the identification of the mechanisms underlying anthracycline resistance remains an unmet clinical need. Here, using patient-derived primary cultures and clinically relevant cellular models that recapitulate acquired anthracycline resistance in AML, we have found that GCN5 (also known as KAT2A) mediates transcriptional upregulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in AML relapse, independently of the DNA-damage response. We demonstrate that anthracyclines fail to induce DNA damage in resistant cells, owing to the loss of expression of their target enzyme, TOP2B; this was caused by DNA-PKcs directly binding to its promoter upstream region as a transcriptional repressor. Importantly, DNA-PKcs kinase activity inhibition re-sensitized AML relapse primary cultures and cells resistant to mitoxantrone, and abrogated their tumorigenic potential in a xenograft mouse model. Taken together, our findings identify a GCN5-DNA-PKcs-TOP2B transcriptional regulatory axis as the mechanism underlying anthracycline resistance, and demonstrate the therapeutic potential of DNA-PKcs inhibition to re-sensitize resistant AML relapse cells to anthracycline.
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MESH Headings
- Humans
- Mice
- Animals
- DNA-Activated Protein Kinase/genetics
- DNA-Activated Protein Kinase/metabolism
- Drug Resistance, Neoplasm/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- DNA Topoisomerases, Type II/genetics
- DNA Topoisomerases, Type II/metabolism
- DNA Topoisomerases, Type II/therapeutic use
- Anthracyclines/pharmacology
- Anthracyclines/therapeutic use
- Antibiotics, Antineoplastic
- Recurrence
- DNA
- Poly-ADP-Ribose Binding Proteins
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Affiliation(s)
- Saket V Mishra
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India
| | - Archisman Banerjee
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India
| | - Debashmita Sarkar
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India
| | - Vishnuvarthan Thangarathnam
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Bhausaheb Bagal
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai 400012, India
| | - Syed K Hasan
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India
- Cell and Tumor Biology Group, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai 410210, India
| | - Shilpee Dutt
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India
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12
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Liu K, Yuan X, Yang T, Deng D, Chen Y, Tang M, Zhang C, Zou Y, Zhang S, Li D, Shi M, Guo Y, Zhou Y, Zhao M, Yang Z, Chen L. Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies. J Med Chem 2024; 67:245-271. [PMID: 38117951 DOI: 10.1021/acs.jmedchem.3c01338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Abstract
Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.
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Affiliation(s)
- Kongjun Liu
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xue Yuan
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Tao Yang
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Dexin Deng
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yong Chen
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Chufeng Zhang
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yurong Zou
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shunjie Zhang
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Dan Li
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Mingsong Shi
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yong Guo
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yanting Zhou
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Min Zhao
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zhuang Yang
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lijuan Chen
- Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
- Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China
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13
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Shaheer K, Prabhu BS, Ali HS, Lakshmanan-M D. Breast cancer cells are sensitized by piperine to radiotherapy through estrogen receptor-α mediated modulation of a key NHEJ repair protein- DNA-PK. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155126. [PMID: 37913642 DOI: 10.1016/j.phymed.2023.155126] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/03/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Non-homologous end joining, an important DNA-double-stranded break repair pathway, plays a prominent role in conferring resistance to radiotherapeutic agents, resulting in cancer progression and relapse. PURPOSE The molecular players involved in the radio-sensitizing effects of piperine and many other phytocompounds remain evasive to a great extent. The study is designed to assess if piperine, a plant alkaloid can alter the radioresistance by modulating the expression of non-homologous end-joining machinery. METHODS AND MATERIALS Estrogen receptor-positive/negative, breast cancer cells were cultured to understand the synergetic effects of piperine with radiotherapy. Cisplatin and Bazedoxifene were used as positive controls. Cells were exposed to γ- radiation using Low Dose gamma Irradiator-2000. The piperine effect on Estrogen receptor modulation, DNA-Damage, DNA-Damage-Response, and apoptosis was done by western blotting, immunofluorescence, yeast-based-estrogen-receptor-LacZ-reporter assay, and nuclear translocation analysis. Micronuclei assay was done for DNA damage and genotoxicity, and DSBs were quantified by γH2AX-foci-staining using confocal microscopy. Flow cytometry analysis was done to determine the cell cycle, mitochondrial membrane depolarization, and Reactive oxygen species generation. Pharmacophore analysis and protein-ligand interaction studies were done using Schrodinger software. Synergy was computed by compusyn-statistical analysis. Standard errors/deviation/significance were computed with GraphPad prism. RESULTS Using piperine, we propose a new strategy for overcoming acquired radioresistance through estrogen receptor-mediated modulation of the NHEJ pathway. This is the first comprehensive study elucidating the mechanism of radio sensitizing potential of piperine. Piperine enhanced the radiation-induced cell death and enhanced the expression and activation of Estrogen receptor β, while Estrogen receptor α expression and activation were reduced. In addition, piperine shares common pharmacophore features with most of the known estrogen agonists and antagonists. It altered the estrogen receptor α/β ratio and the expression of estrogen-responsive proteins of DDR and NHEJ pathway. Enhanced expression of DDR proteins, ATM, p53, and P-p53 with low DNA-PK repair complex (comprising of DNA-PKcs/Ku70/Ku80), resulted in the accumulation of radiation-induced DNA double-stranded breaks (as evidenced by MNi and γH2AX-foci) culminating in cell cycle arrest and mitochondrial-pathway of apoptosis. CONCLUSION In conclusion, our study for the first time reported that piperine sensitizes breast cancer cells to radiation by accumulating DNA breaks, through altering the expression of DNA-PK Complex, and DDR proteins, via selective estrogen receptor modulation, offering a novel strategy for combating radioresistance.
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Affiliation(s)
- Koniyan Shaheer
- Division of Cancer Research and Therapeutics (CaRT), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka 575018, India
| | - Br Swathi Prabhu
- Division of Cancer Research and Therapeutics (CaRT), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka 575018, India
| | - H Shabeer Ali
- Department of Biotechnology and Microbiology, Kannur University, Kannur, Kerala, India
| | - Divya Lakshmanan-M
- Division of Cancer Research and Therapeutics (CaRT), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka 575018, India.
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14
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Wu S, Zhong B, Yang Y, Wang Y, Pan Z. ceRNA networks in gynecological cancers progression and resistance. J Drug Target 2023; 31:920-930. [PMID: 37724808 DOI: 10.1080/1061186x.2023.2261079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/14/2023] [Indexed: 09/21/2023]
Abstract
Gynecological cancers are the second most common types of cancer in women. Clinical diagnosis of these cancers is often delayed or misdiagnosed due to lack of insight into their tumorigenesis mechanism and specific diagnostic biomarkers. Many studies have demonstrated that competing endogenous RNAs (ceRNAs) modulate the progression and resistance of gynecological cancer through microRNA (miRNA)-mediated mechanisms, which affect gene expression in multiple cancer-related pathways. Here we review studies on the involvement of the ceRNA hypothesis in the progression and resistance of gynaecological cancers to validate some ceRNAs as therapeutic targets and predictive biomarkers.
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Affiliation(s)
- Shuqin Wu
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Baoshan Zhong
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yuxin Yang
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yurou Wang
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zezheng Pan
- Faculty of Jiangxi Medical College, Nanchang University, Nanchang, China
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15
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Nickoloff JA, Jaiswal AS, Sharma N, Williamson EA, Tran MT, Arris D, Yang M, Hromas R. Cellular Responses to Widespread DNA Replication Stress. Int J Mol Sci 2023; 24:16903. [PMID: 38069223 PMCID: PMC10707325 DOI: 10.3390/ijms242316903] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors.
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Affiliation(s)
- Jac A. Nickoloff
- Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO 80523, USA
| | - Aruna S. Jaiswal
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
| | - Neelam Sharma
- Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO 80523, USA
| | - Elizabeth A. Williamson
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
| | - Manh T. Tran
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
| | - Dominic Arris
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
| | - Ming Yang
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
| | - Robert Hromas
- Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; (A.S.J.); (M.T.T.); (R.H.)
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16
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Wang R, Sun Y, Li C, Xue Y, Ba X. Targeting the DNA Damage Response for Cancer Therapy. Int J Mol Sci 2023; 24:15907. [PMID: 37958890 PMCID: PMC10648182 DOI: 10.3390/ijms242115907] [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: 09/21/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these mechanisms play a pivotal role in maintaining genomic stability. Defects in the DNA damage response pathways can give rise to various diseases, including cancer. The DNA damage response (DDR) system is instrumental in safeguarding genomic stability. The accumulation of DNA damage and the weakening of DDR function both promote the initiation and progression of tumors. Simultaneously, they offer opportunities and targets for cancer therapeutics. This article primarily elucidates the DNA damage repair pathways and the progress made in targeting key proteins within these pathways for cancer treatment. Among them, poly (ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DDR, and inhibitors targeting PARP1 have garnered extensive attention in anticancer research. By delving into the realms of DNA damage and repair, we aspire to explore more precise and effective strategies for cancer therapy and to seek novel avenues for intervention.
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Affiliation(s)
- Ruoxi Wang
- Center for Cell Structure and Function, Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, China; (R.W.); (Y.S.)
| | - Yating Sun
- Center for Cell Structure and Function, Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, China; (R.W.); (Y.S.)
| | - Chunshuang Li
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun 130024, China; (C.L.); (Y.X.)
| | - Yaoyao Xue
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun 130024, China; (C.L.); (Y.X.)
| | - Xueqing Ba
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun 130024, China; (C.L.); (Y.X.)
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17
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Tan J, Sun X, Zhao H, Guan H, Gao S, Zhou P. Double-strand DNA break repair: molecular mechanisms and therapeutic targets. MedComm (Beijing) 2023; 4:e388. [PMID: 37808268 PMCID: PMC10556206 DOI: 10.1002/mco2.388] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 08/29/2023] [Accepted: 09/08/2023] [Indexed: 10/10/2023] Open
Abstract
Double-strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DNA DSB repair in mammalian cells are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate and compete with one another to achieve effective repair. The DSB repair mechanism depends on numerous regulatory variables. DSB recognition and the recruitment of DNA repair components, for instance, depend on the MRE11-RAD50-NBS1 (MRN) complex and the Ku70/80 heterodimer/DNA-PKcs (DNA-PK) complex, whose control is crucial in determining the DSB repair pathway choice and efficiency of HR and NHEJ. In-depth elucidation on the DSB repair pathway's molecular mechanisms has greatly facilitated for creation of repair proteins or pathways-specific inhibitors to advance precise cancer therapy and boost the effectiveness of cancer radiotherapy. The architectures, roles, molecular processes, and inhibitors of significant target proteins in the DSB repair pathways are reviewed in this article. The strategy and application in cancer therapy are also discussed based on the advancement of inhibitors targeted DSB damage response and repair proteins.
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Affiliation(s)
- Jinpeng Tan
- Hengyang Medical CollegeUniversity of South ChinaHengyangHunan ProvinceChina
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Xingyao Sun
- Hengyang Medical CollegeUniversity of South ChinaHengyangHunan ProvinceChina
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Hongling Zhao
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Hua Guan
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Shanshan Gao
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Ping‐Kun Zhou
- Hengyang Medical CollegeUniversity of South ChinaHengyangHunan ProvinceChina
- Department of Radiation BiologyBeijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
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18
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Lal S, Bhola NE, Sun BC, Chen Y, Huang T, Morton V, Chen KX, Xia S, Zhang H, Parikh NS, Ye Q, Veiby OP, Bellovin DI, Ji Y. Discovery and Characterization of ZL-2201, a Potent, Highly Selective, and Orally Bioavailable Small-molecule DNA-PK Inhibitor. CANCER RESEARCH COMMUNICATIONS 2023; 3:1731-1742. [PMID: 37663435 PMCID: PMC10473160 DOI: 10.1158/2767-9764.crc-23-0304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023]
Abstract
DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation. Significance ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic.
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Affiliation(s)
- Shruti Lal
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Neil E. Bhola
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Bee-Chun Sun
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Yuping Chen
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Tom Huang
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Vivian Morton
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | | | | | | | - Nehal S. Parikh
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - Qiuping Ye
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | - O. Petter Veiby
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
| | | | - Yuhua Ji
- Biologics Discovery, Zai Lab (US) LLC, Menlo Park, California
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19
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Zhang H, Wang X, Ma Y, Zhang Q, Liu R, Luo H, Wang Z. Review of possible mechanisms of radiotherapy resistance in cervical cancer. Front Oncol 2023; 13:1164985. [PMID: 37692844 PMCID: PMC10484717 DOI: 10.3389/fonc.2023.1164985] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023] Open
Abstract
Radiotherapy is one of the main treatments for cervical cancer. Early cervical cancer is usually considered postoperative radiotherapy alone. Radiotherapy combined with cisplatin is the standard treatment for locally advanced cervical cancer (LACC), but sometimes the disease will relapse within a short time after the end of treatment. Tumor recurrence is usually related to the inherent radiation resistance of the tumor, mainly involving cell proliferation, apoptosis, DNA repair, tumor microenvironment, tumor metabolism, and stem cells. In the past few decades, the mechanism of radiotherapy resistance of cervical cancer has been extensively studied, but due to its complex process, the specific mechanism of radiotherapy resistance of cervical cancer is still not fully understood. In this review, we discuss the current status of radiotherapy resistance in cervical cancer and the possible mechanisms of radiotherapy resistance, and provide favorable therapeutic targets for improving radiotherapy sensitivity. In conclusion, this article describes the importance of understanding the pathway and target of radioresistance for cervical cancer to promote the development of effective radiotherapy sensitizers.
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Affiliation(s)
- Hanqun Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Oncology, Guizhou Provincial People's Hospital, Guizhou, China
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Yan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Qiuning Zhang
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Ruifeng Liu
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Hongtao Luo
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Zi Wang
- Department of Oncology, Guizhou Provincial People's Hospital, Guizhou, China
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20
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Taffoni C, Schüssler M, Vila IK, Laguette N. Harnessing the cooperation between DNA-PK and cGAS in cancer therapies: The cooperation between DNA-PK and cGAS shapes tumour immunogenicity. Bioessays 2023; 45:e2300045. [PMID: 37147791 DOI: 10.1002/bies.202300045] [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: 03/08/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/07/2023]
Abstract
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is central for the initiation of anti-tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS-STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA-dependent protein kinase (DNA-PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA-PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non-canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.
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Affiliation(s)
- Clara Taffoni
- IGMM, Université de Montpellier, CNRS, Montpellier, France
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21
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Tan J, Wang W, Liu X, Xu J, Che Y, Liu Y, Hu J, Hu L, Li J, Zhou Q. C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A. Commun Biol 2023; 6:606. [PMID: 37277441 DOI: 10.1038/s42003-023-04957-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 05/19/2023] [Indexed: 06/07/2023] Open
Abstract
C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.
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Affiliation(s)
- Junyang Tan
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Wenjun Wang
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Xinjie Liu
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Jinhong Xu
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Yaping Che
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Yanyan Liu
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Jiaqiao Hu
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Liubing Hu
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China
| | - Jianshuang Li
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China.
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China.
| | - Qinghua Zhou
- The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China.
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, 510632, Guangzhou, Guangdong, China.
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22
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Chen CS, Huang EY. Comparison of Oncologic Outcomes between Radical Hysterectomy and Primary Concurrent Chemoradiotherapy in Women with Bulky IB and IIA Cervical Cancer under Risk Stratification. Cancers (Basel) 2023; 15:cancers15113034. [PMID: 37296994 DOI: 10.3390/cancers15113034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/09/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
PURPOSE To stratify patients according to tumor marker and histology and compare the survival outcome between radical hysterectomy (RH) and primary concurrent chemoradiotherapy (CCRT) in bulky IB and IIA cervical cancer. METHODS A total of 442 patients with cervical cancer were enrolled in the Chang Gung Research Database from January 2002 to December 2017. Patients with squamous cell carcinoma (SCC) and carcinoembryonic antigen (CEA) ≥10 ng/mL, adenocarcinoma (AC), or adenosquamous carcinoma (ASC) were stratified into the high-risk (HR) group. The others were classified into the low-risk (LR) group. We compared oncology outcomes between RH and CCRT in each group. RESULTS In the LR group, 5-year overall survival (OS) and recurrence-free survival (RFS) were 85.9% vs. 85.4% (p = 0.315) and 83.6% vs. 82.5% (p = 0.558) in women treated with RH (n = 99) vs. CCRT (n = 179), respectively. In the HR group, the 5-year OS and RFS were 83.2% vs. 73.3% (p = 0.164) and 75.2% vs. 59.6% (p < 0.036) in patients treated with RH (n = 128) vs. CCRT (n = 36), respectively. Regarding recurrence, locoregional recurrence (LRR) (8.1% vs. 8.6%, p = 0.812) and distant metastases (DM) (17.8% vs. 21%, p = 0.609) were similar between RH and CCRT in the LR group. However, lower LRR (11.6% vs. 26.3%, p = 0.023) but equivalent DM (17.8% vs. 21%, p = 0.609) were found for women undergoing RH compared with CCRT in the HR group. CONCLUSIONS There were similar survival and recurrence rates between both treatment modalities in low-risk patients. Meanwhile, primary surgery with or without adjuvant radiation provides better RFS and local control in women with high-risk features. Further prospective studies are needed to confirm these findings.
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Affiliation(s)
- Chung-Shih Chen
- Departments of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan
| | - Eng-Yen Huang
- Departments of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung City 804, Taiwan
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23
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Reuvers TG, Verkaik NS, Stuurman D, de Ridder C, Groningen MCCV, de Blois E, Nonnekens J. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics 2023; 13:3117-3130. [PMID: 37351169 PMCID: PMC10283055 DOI: 10.7150/thno.82963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/06/2023] [Indexed: 06/24/2023] Open
Abstract
Background: Peptide receptor radionuclide therapy (PRRT) increases progression-free survival and quality of life of neuroendocrine tumor (NET) patients, however complete cures are rare and dose-limiting toxicity has been reported. PRRT induces DNA damage of which DNA double strand breaks (DSBs) are the most cytotoxic. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in DSB repair and its inhibition therefore is a potential way to enhance PRRT efficacy without increasing the dosage. Methods: We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69. Therapy-induced DNA damage response was assessed by analyzing DSB foci levels and cell cycle distributions. In vivo efficacy was investigated in BON1-SSTR2 and NCI-H69 xenografted mice and hematologic and renal toxicity were monitored by blood counts, creatinine levels and analyzing renal morphology. Results: Combining PRRT and AZD7648 significantly decreased viability of BON1-SSTR2, GOT1 and NCI-H69 cells and induced cell death in GOT1 and BON1-SSTR2 cells. A strong effect of AZD7648 on PRRT-induced DSB repair was found. In GOT1 cells, this was accompanied by induction of cell cycle blocks. However, BON1-SSTR2 cells were unable to fully arrest their cell cycle and polyploid cells with high DNA damage levels were detected. In vivo, AZD7648 significantly sensitized BON1-SSTR2 and NCI-H69 xenograft models to PRRT. In addition, combination therapy did not induce significant changes in body weight, blood composition, plasma creatinine levels and renal morphology, indicating the absence of severe acute hematologic and renal toxicity. Conclusion: These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-tolerated therapeutic strategy. Based on our findings, we recommend initiation of phase I/II studies in patients to find a safe and effective combination regimen.
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Affiliation(s)
- Thom G.A. Reuvers
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
| | - Nicole S. Verkaik
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
| | - Debra Stuurman
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
- Department of Urology, Erasmus University Medical Center Rotterdam, The Netherlands
| | - Corrina de Ridder
- Department of Urology, Erasmus University Medical Center Rotterdam, The Netherlands
| | - Marian C. Clahsen-van Groningen
- Department of Pathology, Erasmus University Medical Center Rotterdam, The Netherlands
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Erik de Blois
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
| | - Julie Nonnekens
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands
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24
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Ray U, Gopinatha VK, Sharma S, Goyary L, Choudhary B, Mantelingu K, Rangappa KS, Raghavan SC. Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining. FEBS J 2023; 290:796-820. [PMID: 36048168 DOI: 10.1111/febs.16615] [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: 05/10/2022] [Revised: 07/21/2022] [Accepted: 08/31/2022] [Indexed: 02/04/2023]
Abstract
Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6-diamino-2-mercaptopyrimidin-4-ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27-fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV-dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double-strand breaks inside cells, and improved anti-cancer potential when combined with γ-radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics.
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Affiliation(s)
- Ujjayinee Ray
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Vindya K Gopinatha
- Department of Biochemistry, Indian Institute of Science, Bangalore, India.,Department of Studies in Chemistry, University of Mysore, India
| | - Shivangi Sharma
- Department of Biochemistry, Indian Institute of Science, Bangalore, India.,Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore, India
| | - Laijau Goyary
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Bibha Choudhary
- Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore, India
| | | | - Kanchugarakoppal S Rangappa
- Department of Studies in Chemistry, University of Mysore, India.,Institution of Excellence, Vijnana Bhavana, University of Mysore, India
| | - Sathees C Raghavan
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
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25
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Sensitization of cervical cancer cells to radiation by the cyclin-dependent kinase inhibitor dinaciclib. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:68. [PMID: 36586018 DOI: 10.1007/s12032-022-01890-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/08/2022] [Indexed: 01/01/2023]
Abstract
Dinaciclib is a selective cyclin-dependent kinase inhibitor, but its radiosensitizing effect remains unclear. The aim of this study is to investigate the radiosensitizing effect of Dinaciclib on cervical cancer cells. Two cervical cancer cell lines, Hela and Siha, were selected, and the IC50 was determined by CCK8. The radiosensitizing effect of Dinaciclib was verified by plate cloning assay, and the G2/M phase arrest and apoptosis of IR cells were verified by flow cytometry. Immunofluorescence assay was used to verify the formation of γH2AX foci following DNA damage. Western blot was performed to detect cell cycle, apoptosis, autophagy, and DNA damage-related pathways. Dinaciclib increased the cell sensitivity to IR. IR induced G2/M phase arrest and apoptosis, and Dinaciclib enhanced this effect. Further, Dinaciclib delayed DNA repair, including non-homologous end joining repair and homologous recombination repair, and reduced the expression of DNA repair proteins Ku80 (SiHa cells), Ku70, and RAD51, as well as the expression of apoptotic marker Bcl-2. The expression of autophagy marker Beclin1 induced tumor cell death and increased the formation of DNA damage marker γH2AX foci. Dinaciclib improves the sensitivity of cervical cancer cells to IR by inducing cell cycle arrest, delaying DNA repair, and increasing apoptosis. However, further research is needed to unravel the complexity of DNA repair pathways.
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26
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DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities. Int J Mol Sci 2022; 23:ijms232314672. [PMID: 36499000 PMCID: PMC9735783 DOI: 10.3390/ijms232314672] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients' prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.
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27
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Zhou J, Lei N, Tian W, Guo R, Chen M, Qiu L, Wu F, Li Y, Chang L. Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresistance. Front Oncol 2022; 12:999643. [PMID: 36313645 PMCID: PMC9597614 DOI: 10.3389/fonc.2022.999643] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/27/2022] [Indexed: 08/01/2023] Open
Abstract
Radiotherapy is widely used as an indispensable treatment option for cervical cancer patients. However, radioresistance always occurs and has become a big obstacle to treatment efficacy. The reason for radioresistance is mainly attributed to the high repair ability of tumor cells that overcome the DNA damage caused by radiotherapy, and the increased self-healing ability of cancer stem cells (CSCs). Accumulating findings have demonstrated that the tumor microenvironment (TME) is closely related to cervical cancer radioresistance in many aspects, especially in the metabolic processes. In this review, we discuss radiotherapy in cervical cancer radioresistance, and focus on recent research progress of the TME metabolism that affects radioresistance in cervical cancer. Understanding the mechanism of metabolism in cervical cancer radioresistance may help identify useful therapeutic targets for developing novel therapy, overcome radioresistance and improve the efficacy of radiotherapy in clinics and quality of life of patients.
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Affiliation(s)
- Junying Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ningjing Lei
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wanjia Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengyu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Luojie Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengling Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Li
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Lei Chang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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28
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Guo J, Jin K, Tang T, Liu HM, Xie YA. A new biomarker to enhance the radiosensitivity of hepatocellular cancer: miRNAs. Future Oncol 2022; 18:3217-3228. [PMID: 35968820 DOI: 10.2217/fon-2022-0136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: This review summarizes findings regarding miRNAs that modulate radiation in hepatocellular carcinoma (HCC) and evaluates their potential clinical therapeutic uses. Materials & methods: We searched the relevant English-language medical databases for papers on miRNAs and radiation therapy for tumors to identify miRNAs that are linked with radiosensitivity and radioresistance, focusing on those associated with HCC radiation. Results: There were 88 papers assessed for miRNAs associated with tumor radiation, 56 of which dealt with radiosensitization, 21 with radioresistance and 11 with radiosensitization for HCC. Conclusion: Further work in this area would enable future evaluation of radiation responses and the potential use of miRNAs as therapeutic agents in HCC patients.
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Affiliation(s)
- Ju Guo
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China
| | - Kai Jin
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Ting Tang
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Hong-Mei Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China
| | - Yu-An Xie
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China.,Experimental Research Department, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China.,Guangxi Zhuang Autonomous Region Women & Children Care Hospital, Nanning, Guangxi, 530002, PR China
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Role of p53 in Regulating Radiation Responses. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071099. [PMID: 35888186 PMCID: PMC9319710 DOI: 10.3390/life12071099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 12/12/2022]
Abstract
p53 is known as the guardian of the genome and plays various roles in DNA damage and cancer suppression. The p53 gene was found to express multiple p53 splice variants (isoforms) in a physiological, tissue-dependent manner. The various genes that up- and down-regulated p53 are involved in cell viability, senescence, inflammation, and carcinogenesis. Moreover, p53 affects the radioadaptive response. Given that several studies have already been published on p53, this review presents its role in the response to gamma irradiation by interacting with MDM2, NF-κB, and miRNA, as well as in the inflammation processes, senescence, carcinogenesis, and radiation adaptive responses. Finally, the potential of p53 as a biomarker is discussed.
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30
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Yang X, Yang F, Lan L, Wen N, Li H, Sun X. Potential value of PRKDC as a therapeutic target and prognostic biomarker in pan-cancer. Medicine (Baltimore) 2022; 101:e29628. [PMID: 35801800 PMCID: PMC9259106 DOI: 10.1097/md.0000000000029628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND While protein kinase, DNA-activated, catalytic subunit (PRKDC) plays an important role in double-strand break repair to retain genomic stability, there is still no pan-cancer analysis based on large clinical information on the relationship between PRKDC and different tumors. For the first time, this research used numerous databases to perform a pan-cancer review for PRKDC to explore the possible mechanism of PRKDC in the etiology and outcomes in various tumors. METHODS PRKDC's expression profile and prognostic significance in pan-cancer were investigated based on various databases and online platforms, including TIMER2, GEPIA2, cBioPortal, CPTAC, and SangerBox. We applied the TIMER to identified the interlink of PRKDC and the immune infiltration in assorted tumors, and the SangerBox online platform was adopted to find out the relevance between PRKDC and immune checkpoint genes, tumor mutation burden, and microsatellite instability in tumors. GeneMANIA tool was employed to create a protein-protein interaction analysis, gene set enrichment analysis was conducted to performed gene enrichment analysis. RESULTS Overall, tumor tissue presented a higher degree of PRKDC expression than adjacent normal tissue. Meanwhile, patients with high PRKDC expression have a worse prognosis. PRKDC mutations were present in almost all The Cancer Genome Atlas tumors and might lead to a better survival prognosis. The PRKDC expression level was shown a positive correlation with tumor-infiltrating immune cells. PRKDC high expression cohorts were enriched in "cell cycle" "oocyte meiosis" and "RNA-degradation" signaling pathways. CONCLUSIONS This study revealed the potential value of PRKDC in tumor immunology and as a therapeutic target and prognostic biomarker in pan-cancer.
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Affiliation(s)
- Xiawei Yang
- Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Feng Yang
- Department of Gynocology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Liugen Lan
- Transplant Medical Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Transplantation Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Ning Wen
- Transplant Medical Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Transplantation Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Haibin Li
- Transplant Medical Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Transplantation Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xuyong Sun
- Transplant Medical Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Transplantation Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi Zhuang Autonomous Region, China
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31
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Yao T, Yao Y, Chen Z, Peng Y, Zhong G, Huang C, Li J, Li R. CircCASC15-miR-100-mTOR may influence the cervical cancer radioresistance. Cancer Cell Int 2022; 22:165. [PMID: 35477450 PMCID: PMC9044740 DOI: 10.1186/s12935-022-02573-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 04/06/2022] [Indexed: 11/20/2022] Open
Abstract
Background Cervical cancer has ranked the top one in gynecological malignancies for incidence. Radioresistance is now becoming a leading reason of recurrence. Methods Our microRNA array data indicated that the miRNA-100 level decreased significantly during radioresistance. In this study, we up-regulated miR-100 in Hela and Siha cells by using miR-100 mimics and observed proliferation and invasion. Results It turned out that with overexpression of miR-100, the cells had less invasiveness as well as proliferation. It may target gene mTOR, and it deed reduced EMT. To examine the role of miR-100 in radioresistance, there was no significant result showed by BSP. While the circCASC15 has been identified with sponge function according to RNA pull down and ISH. Conclusion The conclusions indicate miR-100 is a tumor suppressor gene and could be a therapeutic target in radio-resistant cervical cancers.
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Affiliation(s)
- Tingting Yao
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China. .,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University, Guangzhou, China.
| | - Yao Yao
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Zhiliao Chen
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Yongpai Peng
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Guanglei Zhong
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Chunxian Huang
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Jing Li
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Ruixin Li
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
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Kelm JM, Samarbakhsh A, Pillai A, VanderVere-Carozza PS, Aruri H, Pandey DS, Pawelczak KS, Turchi JJ, Gavande NS. Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair. Front Oncol 2022; 12:850883. [PMID: 35463312 PMCID: PMC9020266 DOI: 10.3389/fonc.2022.850883] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 02/22/2022] [Indexed: 01/09/2023] Open
Abstract
The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.
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Affiliation(s)
- Jeremy M. Kelm
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
| | - Amirreza Samarbakhsh
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
| | - Athira Pillai
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
| | | | - Hariprasad Aruri
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
| | - Deepti S. Pandey
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
| | | | - John J. Turchi
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States,NERx Biosciences, Indianapolis, IN, United States,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Navnath S. Gavande
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States,Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States,*Correspondence: Navnath S. Gavande, ; orcid.org/0000-0002-2413-0235
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Dylgjeri E, Kothari V, Shafi AA, Semenova G, Gallagher PT, Guan YF, Pang A, Goodwin JF, Irani S, McCann JJ, Mandigo AC, Chand S, McNair CM, Vasilevskaya I, Schiewer MJ, Lallas CD, McCue PA, Gomella LG, Seifert EL, Carroll JS, Butler LM, Holst J, Kelly WK, Knudsen KE. A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer. Clin Cancer Res 2022; 28:1446-1459. [PMID: 35078861 PMCID: PMC9365345 DOI: 10.1158/1078-0432.ccr-21-1846] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/22/2021] [Accepted: 01/20/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. EXPERIMENTAL DESIGN Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). RESULTS Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. CONCLUSIONS Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.
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Affiliation(s)
- Emanuela Dylgjeri
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Vishal Kothari
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Ayesha A. Shafi
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Galina Semenova
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Peter T. Gallagher
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Yi F. Guan
- School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
| | - Angel Pang
- School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
| | - Jonathan F. Goodwin
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Swati Irani
- South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Adelaide Medical School and Freemasons Foundation Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia
| | - Jennifer J. McCann
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Amy C. Mandigo
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Saswati Chand
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Christopher M. McNair
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Irina Vasilevskaya
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Matthew J. Schiewer
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Costas D. Lallas
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Peter A. McCue
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Leonard G. Gomella
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Erin L. Seifert
- Department of Pathology, Anatomy and Cell Biology and MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jason S. Carroll
- Cancer Research UK Cambridge Research Institute, England, United Kingdom
| | - Lisa M. Butler
- South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Adelaide Medical School and Freemasons Foundation Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia
| | - Jeff Holst
- School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
| | - William K. Kelly
- Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Karen E. Knudsen
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
- Department of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
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Luo J, Chen J, Zhou J, Han K, Li S, Duan J, Cao C, Lin J, Xie D, Wang F. TBX20 inhibits colorectal cancer tumorigenesis by impairing NHEJ‐mediated DNA repair. Cancer Sci 2022; 113:2008-2021. [PMID: 35348274 PMCID: PMC9207377 DOI: 10.1111/cas.15348] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/09/2022] [Accepted: 03/14/2022] [Indexed: 12/04/2022] Open
Abstract
DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T‐box TF family protein, was downregulated with hypermethylation of promoter in early‐stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non‐homologous DNA end joining (NHEJ)‐mediated double‐stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor‐suppressive role of TBX20 by inhibiting NHEJ‐mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early‐stage CRC and a therapeutic target for combination therapy.
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Affiliation(s)
- Jie Luo
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
| | - Jie‐Wei Chen
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
- Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou 510060 China
| | - Jie Zhou
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
| | - Kai Han
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
- Department of Colorectal Surgery Sun Yat‐sen University Cancer Center Guangzhou 510060 China
| | - Si Li
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
| | - Jin‐Ling Duan
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
- Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou 510060 China
| | - Chen‐Hui Cao
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
| | - Jin‐Long Lin
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
| | - Dan Xie
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
- Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou 510060 China
| | - Feng‐Wei Wang
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China
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35
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Inhibiting nonhomologous end-joining repair would promote the antitumor activity of gemcitabine in nonsmall cell lung cancer cell lines. Anticancer Drugs 2022; 33:502-508. [PMID: 35276695 DOI: 10.1097/cad.0000000000001290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Nonsmall cell lung cancer (NSCLC) is a major type of lung cancer. In current study, we aim to evaluate whether the combination of Ku70/80 heterodimer protein inhibitor STL127705 and gemcitabine would be more favorable approach for the treatment of NSCLC compared with monotreatment with gemcitabine. Clongenic survival assay was used to determine the survival and sensitivity to irradiation. H1299 was stained with fluorescein isothiocyanate-Annexin V, and cell apoptosis was measured by flow cytometry. H1299 cells were transfected with nonhomologous end-joining (NHEJ) repair reporter, and stable cell line was selected by puromycin. NHEJ activity was determined based on the intensity of green fluorescent protein. DNA double-strand breaks (DSBs) were determined by the fluorescence intensity of γH2AX using flow cytometry. The mRNA expressions of Ku70 and Ku80 were determined using quantitative real-time PCR. Combination of STL127705 enhanced sensitivity of NSCLC cell lines to irradiation when compared with treatment with gemcitabine alone. However, small cell lung cancer cell line was not affected. H1299 cells treated with STL127705 in combination with gemcitabine showed a significantly increased apoptosis compared with H1299 cells treated with gemcitabine alone. Moreover, STL127705 treatment dramatically reduced NHEJ activity in H1299 cells when compared with gemcitabine single treatment. Increased DSBs were consistently observed in H1299 when treated with the combination of STL127705 and gemcitabine. However, the mRNA levels of Ku70 and Ku80 were upregulated by the combination treatment. It demonstrated that STL127705 enhanced antitumor activity of gemcitabine. Mechanistically, treatment with STL127705 enhanced DNA damage via inhibiting NHEJ pathway, blocking DNA-PK, and forming Ku70/80 heterodimer, eventually leading to tumor cells apoptosis.
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36
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Wan J, Xiao T. MiR-1224 downregulation inhibits OGD/R-induced hippocampal neuron apoptosis through targeting Ku protein. Metab Brain Dis 2022; 37:531-543. [PMID: 34797485 DOI: 10.1007/s11011-021-00873-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022]
Abstract
Ischemic cerebrovascular disease is the main cause of disability due to stroke. This study aimed to investigate the function of miR-1224 in OGD/R-induced hippocampal neuron apoptosis, as well as the regulatory mechanism of miR-1224 in ischemic cerebrovascular disease. The oxygen-glucose deprivation/reperfusion (OGD/R) model of primary mouse hippocampal neurons was established. RT-qPCR detected miR-1224, Ku70 and Ku86 levels. Western blotting was applied to measure the expression of Ku70/86 and apoptosis related proteins. Flow cytometry was used to assess apoptosis. JC-1 fluorescence was performed to test the mitochondrial membrane potential (MMP) in neurons. The double luciferase reporter assay was performed to investigate the relationship between miR-1224 and Ku70/86. OGD/R induced the apoptosis and mitochondrial injury in neuronal cells, while miR-1224 downregulation or Ku70/86 upregulation reversed this phenomenon. Meanwhile, miR-1224 negatively regulated the expression of Ku70/86 in neuronal cells through directly targeting Ku70/86. Furthermore, knockdown of Ku70/86 significantly reversed the inhibitory effect of miR-1224 silencing on apoptosis and mitochondrial injury in OGD/R-treated neuronal cells. Our findings indicated that miR-1224 downregulation suppressed OGD/R-induced hippocampal neuron apoptosis by targeting Ku protein, suggesting that miR-1224 could serve as a new target for ischemic cerebrovascular disease treatment.
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Affiliation(s)
- Juan Wan
- Department of Neurology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan Province, China
| | - Tao Xiao
- Department of Neurosurgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan Province, China.
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37
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Geng A, Xu S, Yao Y, Qian Z, Wang X, Sun J, Zhang J, Shi F, Chen Z, Zhang W, Mao Z, Lu W, Jiang Y. Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells. Cell Cycle 2022; 21:379-391. [PMID: 34985375 PMCID: PMC8855858 DOI: 10.1080/15384101.2021.2020434] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Chrysin, a natural compound isolated from various plants, such as the blue passion flower (Passiflora caerulea L.), exhibits multiple pharmacological activities, such as antitumor, anti-inflammatory and antioxidant activities. Accumulating evidence shows that chrysin inhibits cancer cell growth by inducing apoptosis and regulating cell cycle arrest. However, whether chrysin is involved in regulating genomic stability and its underlying mechanisms in breast cancer cells have not been determined. Here, we demonstrated that chrysin impairs genomic stability in MCF-7 and BT474 cells, inhibits cell survival and enhances the sensitivity of MCF-7 cells to chemotherapeutic drugs. Further experiments revealed that chrysin impairs DNA double-strand break (DSB) repair, resulting in accumulation of DNA damage. Mechanistic studies showed that chrysin inhibits the recruitment of the key NHEJ factor 53BP1 and delays the recruitment of the HR factor RAD51. Thus, we elucidated novel regulatory mechanisms of chrysin in DSB repair and proposed that a combination of chrysin and chemotherapy has curative potential in breast cancers.
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Affiliation(s)
- Anke Geng
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China,CONTACT Anke Geng Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, China
| | - Shiya Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yunxia Yao
- College of Pharmacy, Yanbian University, Yanji, Jilin, China
| | - Zhen Qian
- Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiyue Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiahui Sun
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jingyuan Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Fangfang Shi
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhixi Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Weina Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wen Lu
- Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China,Wen Lu Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ying Jiang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Ying Jiang Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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Zhang L, Zhuang Y, Tu G, Li D, Fan Y, Ye S, Xu J, Zheng M, Wu Y, Wu L. Positive Feedback Regulation of Poly(ADP-ribose) Polymerase 1 and the DNA-PK Catalytic Subunit Affects the Sensitivity of Nasopharyngeal Carcinoma to Etoposide. ACS OMEGA 2022; 7:2571-2582. [PMID: 35097256 PMCID: PMC8793086 DOI: 10.1021/acsomega.1c04379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/24/2021] [Indexed: 06/14/2023]
Abstract
Etoposide (VP-16) is used for the treatment of various cancers, including nasopharyngeal carcinoma (NPC); however, cancers develop resistance to this agent by promoting DNA repair. The DNA-PK (DNA-PKcs) catalytic subunit and poly(ADP-ribose) polymerase 1 (PARP1) mediate acquired resistance and poor survival in NPC cells exposed to DNA damaging agents. DNA repair can alter the sensitivity of NPC cells to DNA damaging agents, and these two enzymes function concomitantly in response to DNA damage in vivo. Therefore, we explored the relationship between DNA-PKcs and PARP1, which may affect NPC cell survival by regulating DNA repair after VP-16 treatment. We performed quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunoassays and found that DNA-PKcs knockdown downregulated the PARP1 and PAR expression. Conversely, PARP1 knockdown reduced DNA-PKcs activity, indicating the mutual regulation between DNA-PKcs and PARP1 in VP-16-induced DNA repair. Moreover, a combination treatment with olaparib (a PARP1 inhibitor) and NU7441 (a DNA-PKcs inhibitor) sensitized NPC cells to VP-16 in vitro and in vivo, suggesting that the combined treatment of olaparib, NU7441, and a DNA-damaging agent may be a successful treatment regimen in patients with NPC.
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Affiliation(s)
- Lingyu Zhang
- Fujian
Medical University Cancer Hospital, Fujian
Cancer Hospital, Fuzhou 350001, China
- Fujian
Key Laboratory of Translational Cancer Medicine, Fuzhou 350001, China
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
- Fujian
Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou 350005, P. R. China
| | - Yingting Zhuang
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
| | - Guihui Tu
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
| | - Ding Li
- Department
of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, P. R. China
| | - Yingjuan Fan
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
| | - Shengnan Ye
- The First
Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China
| | - Jianhua Xu
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
- Fujian
Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou 350005, P. R. China
- Institute
of Materia Medical, Fujian Medical University
(FMU), Fuzhou 350005, P. R. China
| | - Ming Zheng
- Fujian
Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou 350005, P. R. China
| | - Ying Wu
- Key
Laboratory of Natural Drug Pharmacology in Fujian Province, School
of Pharmacy, Fujian Medical University, Fuzhou 350122, P. R. China
| | - Lixian Wu
- Department
of Pharmacology, School of Pharmacy, Fujian
Medical University (FMU), Fuzhou 350005, P. R.
China
- Fujian
Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou 350005, P. R. China
- Institute
of Materia Medical, Fujian Medical University
(FMU), Fuzhou 350005, P. R. China
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Nasrallah NA, Zhou H, Smith PA, Sears CR. DNA Repair Capacity for Personalizing Risk and Treatment Response - Assay Development and Optimization in Human Peripheral Blood Mononuclear Cells (PBMCs). DNA Repair (Amst) 2022; 111:103274. [DOI: 10.1016/j.dnarep.2022.103274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 01/04/2022] [Accepted: 01/16/2022] [Indexed: 11/03/2022]
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40
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Wang M, Chen S, Wei Y, Wei X. DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer. Acta Pharm Sin B 2021; 11:3935-3949. [PMID: 35024317 PMCID: PMC8727896 DOI: 10.1016/j.apsb.2021.07.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/21/2021] [Accepted: 07/09/2021] [Indexed: 11/18/2022] Open
Abstract
A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses in vivo. Moreover, we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide. The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice, with hope to aid the optimization of NSCLC treatment.
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Key Words
- Cell senescence
- Chemosensitization
- DDR, DNA damage response
- DNA repair
- DNA-PK, DNA-dependent protein kinase
- DNA-PKcs, DNA-dependent protein kinase catalytic subunit
- DNA-dependent protein kinase
- DSB, DNA double-strand breaks
- Etoposide
- HR, homologous recombination
- IHC, immunohistochemistry
- LADC, lung adenocarcinoma
- LCLC, large-cell carcinoma
- LSCC, lung squamous cell carcinoma
- M3814
- NHEJ, non homologous end joining
- NSCLC, non-small cell lung cancer
- Non-small cell lung cancer
- Paclitaxel
- dsDNA, double strand DNA
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Wang M, Chen S, Ao D. Targeting DNA repair pathway in cancer: Mechanisms and clinical application. MedComm (Beijing) 2021; 2:654-691. [PMID: 34977872 PMCID: PMC8706759 DOI: 10.1002/mco2.103] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR-targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA-PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR-targeted therapies with other cancer treatment strategies.
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Affiliation(s)
- Manni Wang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Siyuan Chen
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Danyi Ao
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
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42
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Carlos-Reyes A, Muñiz-Lino MA, Romero-Garcia S, López-Camarillo C, Hernández-de la Cruz ON. Biological Adaptations of Tumor Cells to Radiation Therapy. Front Oncol 2021; 11:718636. [PMID: 34900673 PMCID: PMC8652287 DOI: 10.3389/fonc.2021.718636] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
Radiation therapy has been used worldwide for many decades as a therapeutic regimen for the treatment of different types of cancer. Just over 50% of cancer patients are treated with radiotherapy alone or with other types of antitumor therapy. Radiation can induce different types of cell damage: directly, it can induce DNA single- and double-strand breaks; indirectly, it can induce the formation of free radicals, which can interact with different components of cells, including the genome, promoting structural alterations. During treatment, radiosensitive tumor cells decrease their rate of cell proliferation through cell cycle arrest stimulated by DNA damage. Then, DNA repair mechanisms are turned on to alleviate the damage, but cell death mechanisms are activated if damage persists and cannot be repaired. Interestingly, some cells can evade apoptosis because genome damage triggers the cellular overactivation of some DNA repair pathways. Additionally, some surviving cells exposed to radiation may have alterations in the expression of tumor suppressor genes and oncogenes, enhancing different hallmarks of cancer, such as migration, invasion, and metastasis. The activation of these genetic pathways and other epigenetic and structural cellular changes in the irradiated cells and extracellular factors, such as the tumor microenvironment, is crucial in developing tumor radioresistance. The tumor microenvironment is largely responsible for the poor efficacy of antitumor therapy, tumor relapse, and poor prognosis observed in some patients. In this review, we describe strategies that tumor cells use to respond to radiation stress, adapt, and proliferate after radiotherapy, promoting the appearance of tumor radioresistance. Also, we discuss the clinical impact of radioresistance in patient outcomes. Knowledge of such cellular strategies could help the development of new clinical interventions, increasing the radiosensitization of tumor cells, improving the effectiveness of these therapies, and increasing the survival of patients.
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Affiliation(s)
- Angeles Carlos-Reyes
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Marcos A. Muñiz-Lino
- Laboratorio de Patología y Medicina Bucal, Universidad Autónoma Metropolitana Unidad Xochimilco, Mexico City, Mexico
| | - Susana Romero-Garcia
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico, Mexico City
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43
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Berry MR, Fan TM. Target-Based Radiosensitization Strategies: Concepts and Companion Animal Model Outlook. Front Oncol 2021; 11:768692. [PMID: 34746010 PMCID: PMC8564182 DOI: 10.3389/fonc.2021.768692] [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: 09/01/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022] Open
Abstract
External beam radiotherapy is indicated in approximately 50-60% of human cancer patients. The prescribed dose of ionizing radiation that can be delivered to a tumor is determined by the sensitivity of the normal surrounding tissues. Despite dose intensification provided by highly conformal radiotherapy, durable locoregional tumor control remains a clinical barrier for recalcitrant tumor histologies, and contributes to cancer morbidity and mortality. Development of target-based radiosensitization strategies that selectively sensitizes tumor tissue to ionizing radiation is expected to improve radiotherapy efficacy. While exploration of radiosensitization strategies has vastly expanded with technological advances permitting the precise and conformal delivery of radiation, maximal clinical benefit derived from radiotherapy will require complementary discoveries that exploit molecularly-based vulnerabilities of tumor cells, as well as the assessment of investigational radiotherapy strategies in animal models that faithfully recapitulate radiobiologic responses of human cancers. To address these requirements, the purpose of this review is to underscore current and emerging concepts of molecularly targeted radiosensitizing strategies and highlight the utility of companion animal models for improving the predictive value of radiotherapy investigations.
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Affiliation(s)
- Matthew R Berry
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States
| | - Timothy M Fan
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States.,Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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44
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Chen Y, Li Y, Xiong J, Lan B, Wang X, Liu J, Lin J, Fei Z, Zheng X, Chen C. Role of PRKDC in cancer initiation, progression, and treatment. Cancer Cell Int 2021; 21:563. [PMID: 34702253 PMCID: PMC8547028 DOI: 10.1186/s12935-021-02229-8] [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: 07/15/2021] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
The PRKDC gene encodes the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) protein. DNA-PKcs plays an important role in nonhomologous end joining (NHEJ) of DNA double-strand breaks (DSBs) and is also closely related to the establishment of central immune tolerance and the maintenance of chromosome stability. The occurrence and development of different types of tumors and the results of their treatment are also influenced by DNA-PKcs, and it may also predict the results of radiotherapy, chemotherapy, and therapy with immune checkpoint inhibitors (ICIs). Here, we discuss and review the structure and mechanism of action of PRKDC and DNA-PKcs and their relationship with cancer.
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Affiliation(s)
- Yu Chen
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, China
| | - Yi Li
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Jiani Xiong
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Bin Lan
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Shanghai Center for Systems Biomedicine Research, Shanghai Jiao Tong University, Shanghai, China
| | - Xuefeng Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.,The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
| | - Jun Liu
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Jing Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, China
| | - Zhaodong Fei
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Xiaobin Zheng
- Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.,Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Chuanben Chen
- Cancer Bio-Immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China. .,Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, China. .,Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian Province, China.
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45
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Chao OS, Goodman OB. DNA-PKc inhibition overcomes taxane resistance by promoting taxane-induced DNA damage in prostate cancer cells. Prostate 2021; 81:1032-1048. [PMID: 34297853 DOI: 10.1002/pros.24200] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/15/2021] [Accepted: 07/09/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND Overcoming taxane resistance remains a major clinical challenge in metastatic castrate-resistant prostate cancer (mCRPC). Loss of DNA repair proteins is associated with resistance to anti-microtubule agents. We propose that alterations in DNA damage response (DDR) pathway contribute to taxane resistance, and identification of these alterations may provide a potential therapeutic target to resensitize docetaxel-refractory mCRPC to taxane-based therapy. METHODS Alterations in DDR gene expression in our prostate cancer cell line model of docetaxel-resistance (DU145-DxR) derived from DU-145 cells were determined by DDR pathway-specific polymerase chain reaction array and immunoblotting. The PRKDC gene encoding DNA-PKc (DNA-dependent protein kinase catalytic unit), was noted to be overexpressed and evaluated for its role in docetaxel resistance. Cell viability and clonogenic survival of docetaxel-treated DU145-DxR cells were assessed after pharmacologic inhibition of DNA-PKc with three different inhibitors-NU7441, LTURM34, and M3814. Response to second-line cytotoxic agents, cabazitaxel and etoposide upon DNA-PKc inhibition was also tested. The impact of DNA-PKc upregulation on DNA damage repair was evaluated by comet assay and analysis of double-strand breaks marker, γH2AX and Rad51. Lastly, DNA-PKc inhibitor's effect on MDR1 activity was assessed by rhodamine 123 efflux assay. RESULTS DDR pathway-specific gene profiling revealed significant upregulation of PRKDC and CDK7, and downregulation of MSH3 in DU145-DxR cells. Compared to parental DU145, DU145-DxR cells sustained significantly less DNA damage when exposed to etoposide and docetaxel. Pharmacologic inhibition of DNA-PKc, a component of NHEJ repair machinery, with all three inhibitors, significantly resensitized DU145-DxR cells to docetaxel. Furthermore, DNA-PKc inhibition also resensitized DU145-DxR to cabazitaxel and etoposide, which demonstrated cross-resistance. Inhibition of DNA-PKc led to increased DNA damage in etoposide- and docetaxel-treated DU145-DxR cells. Finally, DNA-PKc inhibition did not affect MDR1 activity, indicating that DNA-PKc inhibitors resensitized taxane-resistant cells via an MDR1-independent mechanism. CONCLUSION This study supports a role of DDR genes, particularly, DNA-PKc in promoting resistance to taxanes in mCRPC. Targeting prostatic DNA-PKc may provide a novel strategy to restore taxane sensitivity in taxane-refractory mCRPC.
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Affiliation(s)
- Olivia S Chao
- College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada, USA
| | - Oscar B Goodman
- College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada, USA
- Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA
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46
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Ray U, Raghavan SC. Understanding the DNA double-strand break repair and its therapeutic implications. DNA Repair (Amst) 2021; 106:103177. [PMID: 34325086 DOI: 10.1016/j.dnarep.2021.103177] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 06/25/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
Repair of DNA double-strand breaks (DSBs) and its regulation are tightly integrated inside cells. Homologous recombination, nonhomologous end joining and microhomology mediated end joining are three major DSB repair pathways in mammalian cells. Targeting proteins associated with these repair pathways using small molecule inhibitors can prove effective in tumors, especially those with deregulated repair. Sensitization of cancer to current age therapy including radio and chemotherapy, using small molecule inhibitors is promising and warrant further development. Although several are under clinical trial, till date no repair inhibitor is approved for commercial use in cancer patients, with the exception of PARP inhibitors targeting single-strand break repair. Based on molecular profiling of repair proteins, better prognostic and therapeutic output can be achieved in patients. In the present review, we highlight the different mechanisms of DSB repair, chromatin dynamics to provide repair accessibility and modulation of inhibitors in association with molecular profiling and current gold standard treatment modalities for cancer.
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Affiliation(s)
- Ujjayinee Ray
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Sathees C Raghavan
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
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47
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Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining. Essays Biochem 2021; 64:791-806. [PMID: 32579168 PMCID: PMC7588668 DOI: 10.1042/ebc20190092] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/19/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein-protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein-protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time.
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48
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Vats A, Trejo-Cerro O, Thomas M, Banks L. Human papillomavirus E6 and E7: What remains? Tumour Virus Res 2021; 11:200213. [PMID: 33716206 PMCID: PMC7972986 DOI: 10.1016/j.tvr.2021.200213] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Decades of research on the human papillomavirus oncogenes, E6 and E7, have given us huge amounts of data on their expression, functions and structures. We know much about the very many cellular proteins and pathways that they influence in one way or another. However, much of this information is quite discrete, referring to one activity examined under one condition. It is now time to join the dots to try to understand a larger picture: how, where and when do all these interactions occur... and why? Examining these questions will also show how many of the yet obscure cellular processes work together for cellular and tissue homeostasis in health and disease.
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Affiliation(s)
- Arushi Vats
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Oscar Trejo-Cerro
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Miranda Thomas
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy.
| | - Lawrence Banks
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
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49
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Cabañas Morafraile E, Pérez-Peña J, Fuentes-Antrás J, Manzano A, Pérez-Segura P, Pandiella A, Galán-Moya EM, Ocaña A. Genomic Correlates of DNA Damage in Breast Cancer Subtypes. Cancers (Basel) 2021; 13:cancers13092117. [PMID: 33925616 PMCID: PMC8123819 DOI: 10.3390/cancers13092117] [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: 03/24/2021] [Revised: 04/20/2021] [Accepted: 04/24/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Breast cancer (BC) is the most common invasive tumor in women and the second leading cause of cancer-related death. Therefore, identification of druggable targets to improve current therapies and overcome resistance is a major goal. In this work, we performed an in silico analysis of transcriptomic datasets in breast cancer, and focused on those involved in DNA damage, as were clearly upregulated using gene set enrichment analyses (GSEA), particular the following pathways: ATM/ATR, BARD1 and Fanconi Anemia. BHLHE40, RFWD2, BRIP1, PRKDC, NBN, RNF8, FANCD2, RAD1, BLM, DCLRE1C, UBE2T, CSTF1, MCM7, RFC4, YWHAB, YWHAZ, CDC6, CCNE1, and FANCI genes were amplified/overexpressed in BC, and correlated with detrimental prognosis. Finally, we selected the best transcriptomic signature of genes within this function that associated with clinical outcome to identify functional genomic correlates of outcome. Abstract Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.
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Affiliation(s)
- Esther Cabañas Morafraile
- Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain; (E.C.M.); (J.F.-A.); (A.M.); (P.P.-S.)
| | - Javier Pérez-Peña
- Instituto de Biología Molecular y Celular del Cáncer del CSIC, IBSAL and CIBERONC, 37007 Salamanca, Spain; (J.P.-P.); (A.P.)
| | - Jesús Fuentes-Antrás
- Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain; (E.C.M.); (J.F.-A.); (A.M.); (P.P.-S.)
| | - Aránzazu Manzano
- Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain; (E.C.M.); (J.F.-A.); (A.M.); (P.P.-S.)
| | - Pedro Pérez-Segura
- Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain; (E.C.M.); (J.F.-A.); (A.M.); (P.P.-S.)
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer del CSIC, IBSAL and CIBERONC, 37007 Salamanca, Spain; (J.P.-P.); (A.P.)
| | - Eva M. Galán-Moya
- Translational Oncology Laboratory, Centro Regional de Investigaciones Biomédicas (CRIB) and Nursery School, Campus de Albacete, Universidad de Castilla-La Mancha, 02008 Albacete, Spain;
| | - Alberto Ocaña
- Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain; (E.C.M.); (J.F.-A.); (A.M.); (P.P.-S.)
- Translational Oncology Laboratory, Centro Regional de Investigaciones Biomédicas (CRIB) and Nursery School, Campus de Albacete, Universidad de Castilla-La Mancha, 02008 Albacete, Spain;
- Correspondence:
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50
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Li L, Kumar AK, Hu Z, Guo Z. Small Molecule Inhibitors Targeting Key Proteins in the DNA Damage Response for Cancer Therapy. Curr Med Chem 2021; 28:963-985. [PMID: 32091326 DOI: 10.2174/0929867327666200224102309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 11/22/2022]
Abstract
DNA damage response (DDR) is a complicated interactional pathway. Defects that occur in subordinate pathways of the DDR pathway can lead to genomic instability and cancer susceptibility. Abnormal expression of some proteins in DDR, especially in the DNA repair pathway, are associated with the subsistence and resistance of cancer cells. Therefore, the development of small molecule inhibitors targeting the chief proteins in the DDR pathway is an effective strategy for cancer therapy. In this review, we summarize the development of small molecule inhibitors targeting chief proteins in the DDR pathway, particularly focusing on their implications for cancer therapy. We present the action mode of DDR molecule inhibitors in preclinical studies and clinical cancer therapy, including monotherapy and combination therapy with chemotherapeutic drugs or checkpoint suppression therapy.
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Affiliation(s)
- Lulu Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Alagamuthu Karthick Kumar
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
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