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Zeng H, Fang Z, Feng Y, Su T, Miao W, Wang Z. Self-Assembled Peptide PROTAC Prodrugs Targeting FOXM1 for Cancer Therapy. Mol Pharm 2025. [PMID: 40367368 DOI: 10.1021/acs.molpharmaceut.5c00219] [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: 05/16/2025]
Abstract
Proteolysis-targeting chimeras (PROTACs) represent a promising strategy for addressing ″undruggable″ proteins in cancer therapy. However, challenges such as poor bioavailability, limited cellular permeability, and inadequate targeting hinder their effectiveness. Herein, we present a novel PROTAC prodrug, NFTP, designed for FOXM1 degradation, which leverages self-assembled peptides functionalized with an integrin α-6 ligand to enhance tumor targeting and proteolysis in vivo. NFTP effectively penetrates tumor cells, induces FOXM1 degradation, inhibits cancer cell survival and migration, and promotes apoptosis in vitro. In a 4T1 mouse xenograft model, NFTP demonstrated efficient FOXM1-targeted degradation, significant tumor growth inhibition, and low systemic toxicity. This self-assembling FOXM1 PROTAC platform demonstrates enhanced tumor-targeting precision and superior therapeutic performance in vivo, representing a promising paradigm shift in targeted cancer therapy.
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Affiliation(s)
- Huajie Zeng
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Zhiguo Fang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Yinghua Feng
- Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
| | - Tong Su
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Weibing Miao
- Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Zihua Wang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
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Li Y, Jiang Y, Tong R, Ding B, Ge J, Du K, Sun J, Tang Z, Chen D, Wu J. Thiostrepton suppresses intrahepatic cholangiocarcinoma progression via FOXM1-mediated tumor-associated macrophages reprogramming. Transl Oncol 2025; 54:102327. [PMID: 39986191 PMCID: PMC11904789 DOI: 10.1016/j.tranon.2025.102327] [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: 08/19/2024] [Revised: 12/19/2024] [Accepted: 02/13/2025] [Indexed: 02/24/2025] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with an extremely poor prognosis, highlighting the urgent need for new treatment options. Recent studies increasingly suggest that the Forkhead box M1 (FOXM1) transcription factor may serve as a candidate target for cancer immunotherapy. However, its role and the underlying molecular mechanisms in ICC remain not fully understood. Here, we identify thiostrepton (TST) as a potent FOXM1 inhibitor, capable of exerting "dual anti-tumor" effects in ICC. On one hand, TST effectively suppresses tumor cell proliferation and metastasis. On the other hand, TST treatment improves the tumor immune microenvironment by reprogramming tumor-associated macrophages (TAMs), thereby enhancing anti-tumor immune responses. Mechanistically, TST directly alleviates ICC progression by arresting the cell cycle, promoting apoptosis, and inhibiting the epithelial-mesenchymal transition (EMT) process. Furthermore, TST-treated tumor cells secrete cytokines that drive TAMs repolarization toward the tumor-suppressive M1 phenotype. Overall, our results indicate that FOXM1 can serve as a novel target for ICC immunotherapy. By targeting FOXM1, TST exerts "dual anti-tumor" effects and has the potential to become a promising immunotherapy agent for ICC patients.
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Affiliation(s)
- Yu Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Yifan Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Rongliang Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Bo Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Jiangzhen Ge
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Keyi Du
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Jingqi Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China
| | - Zheng Tang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Diyu Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, PR China.
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, PR China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, PR China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, 310003, PR China.
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Sudaarsan ASK, Ghosh AR. Appraisal of postbiotics in cancer therapy. Front Pharmacol 2024; 15:1436021. [PMID: 39372197 PMCID: PMC11449718 DOI: 10.3389/fphar.2024.1436021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/05/2024] [Indexed: 10/08/2024] Open
Abstract
Cancer remains a multifactorial disease with an increased mortality rate around the world for the past several decades. Despite advancements in treatment strategies, lower survival rates, drug-associated side effects, and drug resistance create a need for novel anticancer agents. Ample evidence shows that imbalances in the gut microbiota are associated with the formation of cancer and its progression. Altering the gut microbiota via probiotics and their metabolites has gained attention among the research community as an alternative therapy to treat cancer. Probiotics exhibit health benefits as well as modulate the immunological and cellular responses in the host. Apart from probiotics, their secreted products like bacteriocins, exopolysaccharides, short-chain fatty acids, conjugated linoleic acid, peptidoglycan, and other metabolites are found to possess anticancer activity. The beneficiary role of these postbiotic compounds is widely studied for characterizing their mechanism and mode of action that reduces cancer growth. The present review mainly focuses on the postbiotic components that are employed against cancer with their reported mechanism of action. It also describes recent research works carried out so far with specific strain and anticancer activity of derived compounds both in vitro and in vivo, validating that the probiotic approach would pave an alternative way to reduce the burden of cancer.
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Meriç N, Kar E, Kar F. 4-Methylthiazole triggers apoptosis and mitochondrial disruption in HL-60 cells. Mol Biol Rep 2024; 51:997. [PMID: 39297923 DOI: 10.1007/s11033-024-09939-y] [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: 07/26/2024] [Accepted: 09/12/2024] [Indexed: 09/21/2024]
Abstract
BACKGROUND Thiazole derivatives are gaining prominence in cancer research due to their potent anti-cancer effects and multifaceted biological activities. In leukemia research, these compounds are particularly studied for their ability to induce apoptosis, disrupt mitochondrial membrane potential (MMP), and modulate cell signaling pathways. METHODS AND RESULTS This study investigates the efficacy of 4-Methylthiazole in inducing apoptosis in HL-60 leukemia cells. Apoptosis was quantified via flow cytometry using FITC Annexin V and propidium iodide staining. Mitochondrial disruption was evaluated through alterations in mitochondrial membrane potential (MMP) as measured by the JC-1 assay. The compound significantly disrupted MMP, activated Caspase-3, and induced the release of Cytochrome C, all of which are critical markers of apoptosis (****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05). Additionally, treatment with 4-Methylthiazole markedly reduced CD45 and CD123 surface markers, indicating significant phenotypic alterations in leukemia cells (****p < 0.0001). High-dose treatment with 4-Methylthiazole significantly increased ROS levels, suggesting elevated oxidative stress and the presence of intracellular free radicals, contributing to its cytotoxic effects (*p < 0.05). A significant rise in TNF-α levels was observed post-treatment, indicating a pro-inflammatory response that may further inhibit leukemia cell viability. While IL-6 levels remained unchanged, a dose-dependent decrease in IL-10 levels was noted, suggesting a reduction in immunosuppressive conditions within the tumor microenvironment (*p < 0.05). CONCLUSIONS Overall, 4-Methylthiazole targets leukemia cells through multiple apoptotic mechanisms and modifies the immune landscape of the tumor microenvironment, enhancing its therapeutic potential. This study highlights the need for further clinical investigation to fully exploit the potential of thiazole derivatives in leukemia treatment.
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Affiliation(s)
- Neslihan Meriç
- Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Kütahya Health Sciences University, Kütahya, Turkey.
| | - Ezgi Kar
- Faculty of Health Sciences, Department of Nutrition and Dietetics, Kütahya Health Sciences University, Kütahya, Turkey
| | - Fatih Kar
- Faculty of Medicine, Department of Biochemistry, Kütahya Health Sciences University, Kütahya, Turkey
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Su G, Yang Q, Zhou H, Huang Y, Nie S, Wang D, Ma G, Zhang S, Kong L, Zou C, Li Y. Thiostrepton as a Potential Therapeutic Agent for Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:9717. [PMID: 39273665 PMCID: PMC11395809 DOI: 10.3390/ijms25179717] [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: 07/29/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
Due to limited drug efficacy and drug resistance, it is urgent to explore effective anti-liver cancer drugs. Repurposing drugs is an efficient strategy, with advantages including reduced costs, shortened development cycles, and assured safety. In this study, we adopted a synergistic approach combining computational and experimental methods and identified the antibacterial drug thiostrepton (TST) as a candidate for an anti-liver cancer drug. Although the anti-tumor capabilities of TST have been reported, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unclear. TST was found here to inhibit the proliferation of HCC cells effectively, arresting the cell cycle and inducing cell apoptosis, as well as suppressing the cell migration. Further, our findings revealed that TST induced mitochondrial impairment, which was demonstrated by destroyed mitochondrial structures, reduced mitochondria, and decreased mitochondrial membrane potential (MMP). TST caused the production of reactive oxygen species (ROS), and the mitochondrial impairment and proliferation inhibition of HCC cells were completely restored by the ROS scavenger N-acetyl-L-cysteine (NAC). Moreover, we discovered that TST induced mitophagy, and autophagy inhibition effectively promoted the anti-cancer effects of TST on HCC cells. In conclusion, our study suggests TST as a promising candidate for the treatment of liver cancers, and these findings provide theoretical support for the further development and potential application of TST in clinical liver cancer therapy.
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Affiliation(s)
- Guifeng Su
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650500, China
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qianqing Yang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Heyang Zhou
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Ying Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Shiyun Nie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Dan Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Guangchao Ma
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Shaohua Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Lingmei Kong
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650500, China
| | - Yan Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650500, China
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
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Wei T, Zeng C, Li Q, Xiao Z, Zhang L, Zhang Q, Ren L. FOXM1/DEPDC1 feedback loop promotes hepatocarcinogenesis and represents promising targets for cancer therapy. Cancer Sci 2024; 115:3041-3053. [PMID: 39004911 PMCID: PMC11463088 DOI: 10.1111/cas.16273] [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: 02/18/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Forkhead box M1 (FOXM1) is a key regulator of mitosis and is identified as an oncogene involved in several kinds of human malignancies. However, how it induces carcinogenesis and related therapeutic approaches remains not fully understood. In this study, we aimed to identify a regulatory axis involving FOXM1 and its target gene DEP domain containing 1 (DEPDC1) and investigate their biological functions. FOXM1 bound to the promoter and transcriptionally induced DEPDC1 expression, in turn, DEPDC1 physically interacted with FOXM1, promoted its nuclear translocation, and reinforced its transcriptional activities. The FOXM1/DEPDC1 axis was indispensable for cancer cells, as evidenced by the fact that DEPDC1 rescued cell growth inhibition caused by FOXM1 knockdown, and silencing DEPDC1 efficiently attenuated tumor growth in a murine hepatocellular carcinoma model. Furthermore, strong positive associations between FOXM1/DEPDC1 axis and poor clinical outcome were observed in human hepatocellular carcinoma samples, further indicating their significance for hepatocarcinogenesis. Finally, we attempted to exploit immunotherapy approaches to target the FOXM1/DEPDC1 axis. Several HLA-A24:02-restricted T-cell epitopes targeting FOXM1 or DEPDC1 were identified through bioinformatic analysis. Then, T cell receptor (TCR)-engineered T cells targeting FOXM1262-270 or DEPDC1294-302 were successfully established and proved to efficiently eradicate tumor cells. Our findings highlight the significance of the FOXM1/DEPDC1 axis in the process of oncogenesis and indicate their potential as immunotherapy targets.
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Affiliation(s)
- Teng Wei
- Cytotherapy LaboratoryShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
| | - Chenquan Zeng
- Cytotherapy LaboratoryShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
| | - Qineng Li
- Cytotherapy LaboratoryShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
| | - Zhiyuan Xiao
- Department of PathologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
| | - Leisheng Zhang
- Jinan Key Laboratory of Medical Cell Bioengineering, Science and Technology Innovation Center, The Fourth People's Hospital of JinanThe Teaching Hospital of Shandong First Medical UniversityJinanChina
- National Health Commission (NHC) Key Laboratory of Diagnosis and Therapy of Gastrointestinal TumorGansu Provincial HospitalLanzhouChina
| | - Qiangnu Zhang
- Biomedicine Research CenterThird Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Lili Ren
- Cytotherapy LaboratoryShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
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Wei B, Yang F, Yu L, Qiu C. Crosstalk between SUMOylation and other post-translational modifications in breast cancer. Cell Mol Biol Lett 2024; 29:107. [PMID: 39127633 DOI: 10.1186/s11658-024-00624-3] [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: 04/06/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Breast cancer represents the most prevalent tumor type and a foremost cause of mortality among women globally. The complex pathophysiological processes of breast cancer tumorigenesis and progression are regulated by protein post-translational modifications (PTMs), which are triggered by different carcinogenic factors and signaling pathways, with small ubiquitin-like modifier (SUMOylation) emerging as a particularly pivotal player in this context. Recent studies have demonstrated that SUMOylation does not act alone, but interacts with other PTMs, such as phosphorylation, ubiquitination, acetylation, and methylation, thereby leading to the regulation of various pathological activities in breast cancer. This review explores novel and existing mechanisms of crosstalk between SUMOylation and other PTMs. Typically, SUMOylation is regulated by phosphorylation to exert feedback control, while also modulates subsequent ubiquitination, acetylation, or methylation. The crosstalk pairs in promoting or inhibiting breast cancer are protein-specific and site-specific. In mechanism, alterations in amino acid side chain charges, protein conformations, or the occupation of specific sites at specific domains or sites underlie the complex crosstalk. In summary, this review centers on elucidating the crosstalk between SUMOylation and other PTMs in breast cancer oncogenesis and progression and discuss the molecular mechanisms contributing to these interactions, offering insights into their potential applications in facilitating novel treatments for breast cancer.
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Affiliation(s)
- Bajin Wei
- The Department of Breast Surgery, Key Laboratory of Organ Transplantation, Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Luyang Yu
- MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zijingang Campus, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
| | - Cong Qiu
- MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zijingang Campus, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
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Wang WD, Zeng CY, Shang Y, Ni J, Li GJ, Li LP, Xi SH, Chen SZ. Thiostrepton suppresses triple-negative breast cancer through downregulating c-FLIP/SMAD2/3 signaling pathway. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:945-954. [PMID: 38634704 DOI: 10.1080/10286020.2024.2343420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 04/10/2024] [Indexed: 04/19/2024]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis of breast cancer. Thiostrepton exerts anti-tumor activities against several cancers including TNBC. Herein we discussed the new molecular mechanisms of thiostrepton in TNBC. Thiostrepton inhibited MDA-MB-231 cell viability, accompanied by a decrease of c-FLIP and p-SMAD2/3. c-FLIP overexpression reduced the sensitivity of MDA-MB-231 cells to thiostrepton, while SMAD2/3 knockdown increased the sensitivity of MDA-MB-231 cells to thiostrepton. Moreover, c-FLIP overexpression significantly increased the expression and phosphorylation of SMAD2/3 proteins and vice versa. In conclusion, our study reveals c-FLIP/SMAD2/3 signaling pathway as a novel mechanism of antitumor activity of thiostrepton.
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Affiliation(s)
- Wen-Die Wang
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Chao-Yang Zeng
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Yue Shang
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Jun Ni
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Gao-Jie Li
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Li-Ping Li
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shuo-Han Xi
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shu-Zhen Chen
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
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9
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Hakata T, Yamauchi I, Kosugi D, Sugawa T, Fujita H, Okamoto K, Ueda Y, Fujii T, Taura D, Inagaki N. High-throughput Screening for Cushing Disease: Therapeutic Potential of Thiostrepton via Cell Cycle Regulation. Endocrinology 2024; 165:bqae089. [PMID: 39058910 DOI: 10.1210/endocr/bqae089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/03/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024]
Abstract
Cushing disease is a life-threatening disorder caused by autonomous secretion of ACTH from pituitary neuroendocrine tumors (PitNETs). Few drugs are indicated for inoperative Cushing disease, in particular that due to aggressive PitNETs. To explore agents that regulate ACTH-secreting PitNETs, we conducted high-throughput screening (HTS) using AtT-20, a murine pituitary tumor cell line characterized by ACTH secretion. For the HTS, we constructed a live cell-based ACTH reporter assay for high-throughput evaluation of ACTH changes. This assay was based on HEK293T cells overexpressing components of the ACTH receptor and a fluorescent cAMP biosensor, with high-throughput acquisition of fluorescence images. We treated AtT-20 cells with compounds and assessed ACTH concentrations in the conditioned media using the reporter assay. Of 2480 screened bioactive compounds, over 50% inhibition of ACTH secreted from AtT-20 cells was seen with 84 compounds at 10 μM and 20 compounds at 1 μM. Among these hit compounds, we focused on thiostrepton (TS) and determined its antitumor effects in both in vitro and in vivo xenograft models of Cushing disease. Transcriptome and flow cytometry analyses revealed that TS administration induced AtT-20 cell cycle arrest at the G2/M phase, which was mediated by FOXM1-independent mechanisms including downregulation of cyclins. Simultaneous TS administration with a cyclin-dependent kinase 4/6 inhibitor that affected the cell cycle at the G0/1 phase showed cooperative antitumor effects. Thus, TS is a promising therapeutic agent for Cushing disease. Our list of hit compounds and new mechanistic insights into TS effects serve as a valuable foundation for future research.
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Affiliation(s)
- Takuro Hakata
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Ichiro Yamauchi
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Daisuke Kosugi
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Taku Sugawa
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Haruka Fujita
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kentaro Okamoto
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yohei Ueda
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Toshihito Fujii
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Daisuke Taura
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
| | - Nobuya Inagaki
- Medical Research Institute, Kitano Hospital, PIIF Tazuke-kofukai, Kita-ku, Osaka 530-8480, Japan
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10
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Battistini C, Kenny HA, Zambuto M, Nieddu V, Melocchi V, Decio A, Lo Riso P, Villa CE, Gatto A, Ghioni M, Porta FM, Testa G, Giavazzi R, Colombo N, Bianchi F, Lengyel E, Cavallaro U. Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness. Cell Death Dis 2024; 15:370. [PMID: 38806454 PMCID: PMC11133450 DOI: 10.1038/s41419-024-06767-7] [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: 04/09/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 05/30/2024]
Abstract
In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we leverage a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. We discovered that the pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/cancer stem cells crosstalk, contributing to the identification of tumor vulnerabilities.
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Affiliation(s)
- Chiara Battistini
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Hilary A Kenny
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, 60637, USA
| | - Melissa Zambuto
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Valentina Nieddu
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Valentina Melocchi
- Cancer Biomarkers Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy
| | - Alessandra Decio
- Laboratory of Cancer Metastasis Therapeutics, Mario Negri Institute for Pharmacological Research - IRCCS, 20156, Milan, Italy
| | - Pietro Lo Riso
- Department of Experimental Oncology, European Institute of Oncology IRCSS, Milan, Italy
| | | | - Alessia Gatto
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Mariacristina Ghioni
- Division of Pathology, European Institute of Oncology IRCCS, 20141, Milan, Italy
| | - Francesca M Porta
- Division of Pathology, European Institute of Oncology IRCCS, 20141, Milan, Italy
- School of Pathology, University of Milan, 20122, Milan, Italy
| | - Giuseppe Testa
- Department of Experimental Oncology, European Institute of Oncology IRCSS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Raffaella Giavazzi
- Laboratory of Cancer Metastasis Therapeutics, Mario Negri Institute for Pharmacological Research - IRCCS, 20156, Milan, Italy
| | - Nicoletta Colombo
- Division of Gynecologic Oncology, European Institute of Oncology IRCCS, 20141, Milan, Italy
- University of Milan-Bicocca, 20126, Milan, Italy
| | - Fabrizio Bianchi
- Cancer Biomarkers Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy
| | - Ernst Lengyel
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, 60637, USA
| | - Ugo Cavallaro
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCCS, 20139, Milan, Italy.
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11
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Liu C, Vorderbruggen M, Muñoz-Trujillo C, Kim SH, Katzenellenbogen JA, Katzenellenbogen BS, Karpf AR. NB compounds are potent and efficacious FOXM1 inhibitors in high-grade serous ovarian cancer cells. J Ovarian Res 2024; 17:94. [PMID: 38704607 PMCID: PMC11069232 DOI: 10.1186/s13048-024-01421-4] [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: 01/30/2024] [Accepted: 04/20/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. RESULTS We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. CONCLUSIONS NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.
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Affiliation(s)
- Cassie Liu
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
| | - Makenzie Vorderbruggen
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
| | - Catalina Muñoz-Trujillo
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA
| | - Sung Hoon Kim
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - John A Katzenellenbogen
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Benita S Katzenellenbogen
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Adam R Karpf
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA.
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12
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Reuben RC, Torres C. Bacteriocins: potentials and prospects in health and agrifood systems. Arch Microbiol 2024; 206:233. [PMID: 38662051 PMCID: PMC11045635 DOI: 10.1007/s00203-024-03948-y] [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: 02/02/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/26/2024]
Abstract
Bacteriocins are highly diverse, abundant, and heterogeneous antimicrobial peptides that are ribosomally synthesized by bacteria and archaea. Since their discovery about a century ago, there has been a growing interest in bacteriocin research and applications. This is mainly due to their high antimicrobial properties, narrow or broad spectrum of activity, specificity, low cytotoxicity, and stability. Though initially used to improve food quality and safety, bacteriocins are now globally exploited for innovative applications in human, animal, and food systems as sustainable alternatives to antibiotics. Bacteriocins have the potential to beneficially modulate microbiota, providing viable microbiome-based solutions for the treatment, management, and non-invasive bio-diagnosis of infectious and non-infectious diseases. The use of bacteriocins holds great promise in the modulation of food microbiomes, antimicrobial food packaging, bio-sanitizers and antibiofilm, pre/post-harvest biocontrol, functional food, growth promotion, and sustainable aquaculture. This can undoubtedly improve food security, safety, and quality globally. This review highlights the current trends in bacteriocin research, especially the increasing research outputs and funding, which we believe may proportionate the soaring global interest in bacteriocins. The use of cutting-edge technologies, such as bioengineering, can further enhance the exploitation of bacteriocins for innovative applications in human, animal, and food systems.
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Affiliation(s)
- Rine Christopher Reuben
- Area of Biochemistry and Molecular Biology, OneHealth-UR Research Group, University of La Rioja, 26006, Logroño, Spain.
| | - Carmen Torres
- Area of Biochemistry and Molecular Biology, OneHealth-UR Research Group, University of La Rioja, 26006, Logroño, Spain
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13
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Feng F, Duan Q, Jiang X, Kao X, Zhang D. DendroX: multi-level multi-cluster selection in dendrograms. BMC Genomics 2024; 25:134. [PMID: 38308243 PMCID: PMC10835886 DOI: 10.1186/s12864-024-10048-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/24/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Cluster heatmaps are widely used in biology and other fields to uncover clustering patterns in data matrices. Most cluster heatmap packages provide utility functions to divide the dendrograms at a certain level to obtain clusters, but it is often difficult to locate the appropriate cut in the dendrogram to obtain the clusters seen in the heatmap or computed by a statistical method. Multiple cuts are required if the clusters locate at different levels in the dendrogram. RESULTS We developed DendroX, a web app that provides interactive visualization of a dendrogram where users can divide the dendrogram at any level and in any number of clusters and pass the labels of the identified clusters for functional analysis. Helper functions are provided to extract linkage matrices from cluster heatmap objects in R or Python to serve as input to the app. A graphic user interface was also developed to help prepare input files for DendroX from data matrices stored in delimited text files. The app is scalable and has been tested on dendrograms with tens of thousands of leaf nodes. As a case study, we clustered the gene expression signatures of 297 bioactive chemical compounds in the LINCS L1000 dataset and visualized them in DendroX. Seventeen biologically meaningful clusters were identified based on the structure of the dendrogram and the expression patterns in the heatmap. We found that one of the clusters consisting of mostly naturally occurring compounds is not previously reported and has its members sharing broad anticancer, anti-inflammatory and antioxidant activities. CONCLUSIONS DendroX solves the problem of matching visually and computationally determined clusters in a cluster heatmap and helps users navigate among different parts of a dendrogram. The identification of a cluster of naturally occurring compounds with shared bioactivities implicates a convergence of biological effects through divergent mechanisms.
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Affiliation(s)
- Feiling Feng
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Qiaonan Duan
- Department of Clinical and Translational Medicine, 3D Medicines Inc., Shanghai, China
| | - Xiaoqing Jiang
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaoming Kao
- Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Dadong Zhang
- Department of Clinical and Translational Medicine, 3D Medicines Inc., Shanghai, China.
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14
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Lunger C, Shen Z, Holcombe H, Mannion AJ, Dzink-Fox J, Kurnick S, Feng Y, Muthupalani S, Carrasco SE, Wilson KT, Peek RM, Piazuelo MB, Morgan DR, Armijo AL, Mammoliti M, Wang TC, Fox JG. Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer. Microbiol Spectr 2024; 12:e0345023. [PMID: 38014984 PMCID: PMC10783005 DOI: 10.1128/spectrum.03450-23] [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] [Accepted: 10/19/2023] [Indexed: 11/29/2023] Open
Abstract
IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.
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Affiliation(s)
- Courtney Lunger
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Hilda Holcombe
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Anthony J. Mannion
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - JoAnn Dzink-Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Susanna Kurnick
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sebastian E. Carrasco
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas R. Morgan
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Amanda L. Armijo
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Melissa Mammoliti
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Timothy C. Wang
- Division of Gastroenterology and Irvine Cancer Research Center, Columbia University, New York, New York, USA
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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15
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Xu R, Lee YJ, Kim CH, Min GH, Kim YB, Park JW, Kim DH, Kim JH, Yim H. Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1. J Exp Clin Cancer Res 2023; 42:302. [PMID: 37968723 PMCID: PMC10652615 DOI: 10.1186/s13046-023-02872-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/26/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Understanding the mechanism behind immune cell plasticity in cancer metastasis is crucial for identifying key regulators. Previously we found that mitotic factors regulate epithelial-mesenchymal transition, but how these factors convert to metastatic players in the tumor microenvironment (TME) is not fully understood. METHODS The clinical importance of mitotic factors was analyzed by heatmap analysis, a KM plot, and immunohistochemistry in lung adenocarcinoma (LUAD) patients. Immunoprecipitation, LC-MS/MS, kinase assay, and site-directed mutagenesis were performed for the interaction and phosphorylation. A tail-vein injection mouse model, Transwell-based 3D culture, microarray analysis, coculture with monocytes, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated FoxM1 in metastasis of TME. RESULTS The phosphorylated FoxM1 at Ser25 by PLK1 acquires the reprogramming ability to stimulate the invasive traits in cancer and influence immune cell plasticity. This invasive form of p-FoxM1 upregulates the expression of IL1A/1B, VEGFA, and IL6 by direct activation, recruiting monocytes and promoting the polarization of M2d-like tumor-associated macrophages (TAMs). Upregulation of PD-L1 in LUAD having phosphomimetic FoxM1 facilitates immune evasion. In invasive LUAD with phosphomimetic FoxM1, IFITM1 is the most highly expressed through the activation of the STING-TBK1-IRF3 signaling, which enhances FoxM1-mediated signaling. Clinically, higher expression of FOXM1, PLK1, and IFITM1 is inversely correlated with the survival rate of advanced LUAD patients, providing a promising therapeutic strategy for the treatment of LUAD. CONCLUSION FoxM1-based therapy would be a potential therapeutic strategy for LUAD to reduce TAM polarization, immune escape, and metastasis, since FoxM1 functions as a genetic reprogramming factor reinforcing LUAD malignancy in the TME.
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Affiliation(s)
- Rong Xu
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Young-Joo Lee
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Chang-Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Ga-Hong Min
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Jung-Won Park
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Dae-Hoon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Jung-Hyun Kim
- Division of Intractable Diseases Research, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju, Chungcheongbuk-Do, 28160, Republic of Korea
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea.
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16
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Raghuwanshi S, Gartel AL. Small-molecule inhibitors targeting FOXM1: Current challenges and future perspectives in cancer treatments. Biochim Biophys Acta Rev Cancer 2023; 1878:189015. [PMID: 37913940 DOI: 10.1016/j.bbcan.2023.189015] [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: 08/26/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
Forkhead box (FOX) protein M1 (FOXM1) is a critical proliferation-associated transcription factor (TF) that is aberrantly overexpressed in the majority of human cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in, cell proliferation, cell migration, invasion, angiogenesis and metastasis. The FOXM1 as a TF directly or indirectly regulates the expression of several target genes whose dysregulation is associated with almost all hallmarks of cancer. Moreover, FOXM1 expression is associated with chemoresistance to different anti-cancer drugs. Several studies have confirmed that suppression of FOXM1 enhanced the drug sensitivity of various types of cancer cells. Current data suggest that small molecule inhibitors targeting FOXM1 in combination with anticancer drugs may represent a novel therapeutic strategy for chemo-resistant cancers. In this review, we discuss the clinical utility of FOXM1, further, we summarize and discuss small-molecule inhibitors targeting FOXM1 and categorize them according to their mechanisms of targeting FOXM1. Despite great progress, small-molecule inhibitors targeting FOXM1 face many challenges, and we present here all small-molecule FOXM1 inhibitors in different stages of development. We discuss the current challenges and provide insights on the future application of FOXM1 inhibition to the clinic.
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Affiliation(s)
- Sanjeev Raghuwanshi
- University of Illinois at Chicago, Department of Medicine, Chicago, IL 60612, USA
| | - Andrei L Gartel
- University of Illinois at Chicago, Department of Medicine, Chicago, IL 60612, USA.
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17
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Tran GB, Ding J, Ye B, Liu M, Yu Y, Zha Y, Dong Z, Liu K, Sudarshan S, Ding HF. Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma. Cancer Res 2023; 83:2248-2261. [PMID: 37057874 PMCID: PMC10320471 DOI: 10.1158/0008-5472.can-22-3450] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/14/2023] [Accepted: 04/12/2023] [Indexed: 04/15/2023]
Abstract
High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma. SIGNIFICANCE Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091.
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Affiliation(s)
- Gia-Buu Tran
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
- O'Neal Comprehensive Cancer Center, Birmingham, Alabama
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Jane Ding
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
- O'Neal Comprehensive Cancer Center, Birmingham, Alabama
| | - Bingwei Ye
- Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Mengling Liu
- Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China
| | - Yajie Yu
- Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China
| | - Yunhong Zha
- Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China
| | - Zheng Dong
- Department of Cell Biology and Anatomy, Augusta University, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Sunil Sudarshan
- O'Neal Comprehensive Cancer Center, Birmingham, Alabama
- Department of Urology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Han-Fei Ding
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
- O'Neal Comprehensive Cancer Center, Birmingham, Alabama
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18
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Han XY, Zhou ZY, Li SY, Xue ST. Advances in inhibitors of potential tumor target FOXM1. Future Med Chem 2023; 15:809-812. [PMID: 37226453 DOI: 10.4155/fmc-2023-0118] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Affiliation(s)
- Xiao-Yang Han
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Zi-Ying Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Si-Yan Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Si-Tu Xue
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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19
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Kojasoy V, Tantillo DJ. Importance of Noncovalent Interactions Involving Sulfur Atoms in Thiopeptide Antibiotics─Glycothiohexide α and Nocathiacin I. J Phys Chem A 2023; 127:2081-2090. [PMID: 36855831 DOI: 10.1021/acs.jpca.2c07600] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur-π interactions, and S-lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor-acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.
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Affiliation(s)
- Volga Kojasoy
- Department of Chemistry, University of California─Davis, Davis, California 95616, United States
| | - Dean J Tantillo
- Department of Chemistry, University of California─Davis, Davis, California 95616, United States
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20
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Donovan J, Deng Z, Bian F, Shukla S, Gomez-Arroyo J, Shi D, Kalinichenko VV, Kalin TV. Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1. Front Oncol 2023; 13:1112859. [PMID: 36816948 PMCID: PMC9933126 DOI: 10.3389/fonc.2023.1112859] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/06/2023] [Indexed: 02/05/2023] Open
Abstract
Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NPFA), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NPFA nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity.
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Affiliation(s)
- Johnny Donovan
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Zicheng Deng
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, United States,Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Fenghua Bian
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Samriddhi Shukla
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Jose Gomez-Arroyo
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,Division of Pulmonary and Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Donglu Shi
- The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, United States
| | - Vladimir V. Kalinichenko
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Tanya V. Kalin
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,*Correspondence: Tanya V. Kalin,
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21
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Li Z, Yang HY, Zhang XL, Zhang X, Huang YZ, Dai XY, Shi L, Zhou GR, Wei JF, Ding Q. Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway. J Exp Clin Cancer Res 2022; 41:168. [PMID: 35524313 PMCID: PMC9077852 DOI: 10.1186/s13046-022-02373-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. Methods Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. Results We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02373-7.
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22
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Liu SX, Zhou Y, Zhao L, Zhou LS, Sun J, Liu GJ, Du YS, Zhou YN. Thiostrepton confers protection against reactive oxygen species-related apoptosis by restraining FOXM1-triggerred development of gastric cancer. Free Radic Biol Med 2022; 193:385-404. [PMID: 36152915 DOI: 10.1016/j.freeradbiomed.2022.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 09/06/2022] [Accepted: 09/17/2022] [Indexed: 12/01/2022]
Abstract
Gastric cancer is a leading cause of tumor-associated death worldwide. Metastasis and chemoresistance are crucial barriers for gastric cancer treatment. The Forkhead Box M1 (FOXM1) transcription factor has been reported as a promising treatment target for various types of tumors, but its effects on gastric cancer progression are not fully understood. In the present study, we found that FOXM1 expression levels were significantly up-regulated in human gastric cancer cell lines and tissues, and its expression was much higher in patients with metastasis. We then found that suppressing FOXM1 with its inhibitor thiostrepton (THIO) significantly reduced the proliferation of gastric cancer cells, while induced G0/G1 and apoptosis. Moreover, reactive oxygen species (ROS) production, mitochondrial impair and autophagy were remarkably provoked in gastric cancer cells treated with THIO, which were required for the regulation of apoptotic cell death. Furthermore, THIO exposure considerably suppressed the migration, invasion and angiogenesis in gastric cancer cells. The inhibitory effects of THIO on tumor growth and metastasis were confirmed in an established gastric cancer xenograft mouse model without detectable toxicity. Intriguingly, our in vitro studies showed that the anti-cancer effects of THIO on gastric cancer were almost abolished upon FOXM1 over-expression, indicating the necessity of FOXM1 suppression in THIO-inhibited tumor growth. In addition, higher FOXM1 expression was detected in gastric cancer cells with chemoresistance. Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.
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Affiliation(s)
- Shi-Xiong Liu
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Yun Zhou
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Li Zhao
- Department of Medical Ultrasound, The Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, 730020, China
| | - Ling-Shan Zhou
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Jie Sun
- Department of Geriatrics (I), The First Hospital of Lanzhou University, Lanzho, 730000, China
| | - Ge-Jing Liu
- Department of Geriatrics (I), The First Hospital of Lanzhou University, Lanzho, 730000, China
| | - Ying-Shi Du
- Department of Geriatrics (I), The First Hospital of Lanzhou University, Lanzho, 730000, China
| | - Yong-Ning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
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23
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Madhi H, Lee J, Choi YE, Li Y, Kim MH, Choi Y, Goh S. FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD-L1 Expression and Cell Proliferation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202702. [PMID: 35975458 PMCID: PMC9561767 DOI: 10.1002/advs.202202702] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/14/2022] [Indexed: 05/31/2023]
Abstract
Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3+ T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.
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Affiliation(s)
- Hamadi Madhi
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
- Department of AnatomyGraduate School of Medical SciencesYonsei University College of MedicineSeoul03722Republic of Korea
| | - Jeon‐Soo Lee
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
| | - Young Eun Choi
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
| | - Yan Li
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
| | - Myoung Hee Kim
- Department of AnatomyGraduate School of Medical SciencesYonsei University College of MedicineSeoul03722Republic of Korea
| | - Yongdoo Choi
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
| | - Sung‐Ho Goh
- Research InstituteNational Cancer Center323 Ilsan‐ro, GoyangGyeonggi‐Do10408Republic of Korea
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24
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Ongpipattanakul C, Desormeaux EK, DiCaprio A, van der Donk WA, Mitchell DA, Nair SK. Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides. Chem Rev 2022; 122:14722-14814. [PMID: 36049139 PMCID: PMC9897510 DOI: 10.1021/acs.chemrev.2c00210] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a natural product class that has undergone significant expansion due to the rapid growth in genome sequencing data and recognition that they are made by biosynthetic pathways that share many characteristic features. Their mode of actions cover a wide range of biological processes and include binding to membranes, receptors, enzymes, lipids, RNA, and metals as well as use as cofactors and signaling molecules. This review covers the currently known modes of action (MOA) of RiPPs. In turn, the mechanisms by which these molecules interact with their natural targets provide a rich set of molecular paradigms that can be used for the design or evolution of new or improved activities given the relative ease of engineering RiPPs. In this review, coverage is limited to RiPPs originating from bacteria.
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Affiliation(s)
- Chayanid Ongpipattanakul
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Emily K. Desormeaux
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Adam DiCaprio
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Wilfred A. van der Donk
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Douglas A. Mitchell
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Microbiology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Satish K. Nair
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
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25
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Demirtas Korkmaz F, Dogan Turacli I, Esendagli G, Ekmekci A. Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis. Mol Biol Rep 2022; 49:10387-10397. [PMID: 36097108 DOI: 10.1007/s11033-022-07751-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metastatic parameters in vitro and in vivo. METHODS Cell viability was determined by MTT assay. Immunoblotting and immunohistochemistry was used to assess metastasis-related protein expressions in 4T1 cells and its allograft tumor model in BALB/c mice. In vivo uPA activity was determined by enzymatic methods. RESULTS Both inhibitors were effective on the expressions of FoxM1, ERK, p-ERK, Twist, E-cadherin, and Vimentin alone or in combination in vitro. THIO significantly decreased 4T1 cell migration and changed the cell morphology from mesenchymal-like to epithelial-like structure. THIO was more effective than in combination with SEL in terms of metastatic protein expressions in vivo. THIO alone significantly inhibited mean tumor growth, decreased lung metastasis rate and tumor foci, however, no significant changes in these parameters were observed in the combined group. Immunohistochemically, FoxM1 expression intensity was decreased with THIO and its combination with SEL in the tumors. CONCLUSIONS This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.
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Affiliation(s)
- Funda Demirtas Korkmaz
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey. .,Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, 28100, Turkey.
| | - Irem Dogan Turacli
- Department of Medical Biology, Faculty of Medicine, Ufuk University, Ankara, Turkey
| | - Guldal Esendagli
- Department of Medical Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Abdullah Ekmekci
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey
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26
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Yang EJ, Park JH, Cho HJ, Hwang JA, Woo SH, Park CH, Kim SY, Park JT, Park SC, Hwang D, Lee YS. Co-inhibition of ATM and ROCK synergistically improves cell proliferation in replicative senescence by activating FOXM1 and E2F1. Commun Biol 2022; 5:702. [PMID: 35835838 PMCID: PMC9283421 DOI: 10.1038/s42003-022-03658-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 06/29/2022] [Indexed: 12/30/2022] Open
Abstract
The multifaceted nature of senescent cell cycle arrest necessitates the targeting of multiple factors arresting or promoting the cell cycle. We report that co-inhibition of ATM and ROCK by KU-60019 and Y-27632, respectively, synergistically increases the proliferation of human diploid fibroblasts undergoing replicative senescence through activation of the transcription factors E2F1 and FOXM1. Time-course transcriptome analysis identified FOXM1 and E2F1 as crucial factors promoting proliferation. Co-inhibition of the kinases ATM and ROCK first promotes the G2/M transition via FOXM1 activation, leading to accumulation of cells undergoing the G1/S transition via E2F1 activation. The combination of both inhibitors increased this effect more significantly than either inhibitor alone, suggesting synergism. Our results demonstrate a FOXM1- and E2F1-mediated molecular pathway enhancing cell cycle progression in cells with proliferative potential under replicative senescence conditions, and treatment with the inhibitors can be tested for senomorphic effect in vivo.
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Affiliation(s)
- Eun Jae Yang
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Ji Hwan Park
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Hyun-Ji Cho
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Jeong-A Hwang
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Seung-Hwa Woo
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Chi Hyun Park
- Department of Computer Science and Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Sung Young Kim
- Department of Biochemistry, Konkuk University School of Medicine, Seoul, 05029, Korea
| | - Joon Tae Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Sang Chul Park
- Well Aging Research Center, Division of Biotechnology, DGIST, Daegu, 42988, Republic of Korea.
- The Future Life & Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju, 61469, Republic of Korea.
| | - Daehee Hwang
- Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
| | - Young-Sam Lee
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea.
- Well Aging Research Center, Division of Biotechnology, DGIST, Daegu, 42988, Republic of Korea.
- New Biology Research Center, DGIST, Daegu, 42988, Republic of Korea.
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27
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CDI Exerts Anti-Tumor Effects by Blocking the FoxM1-DNA Interaction. Biomedicines 2022; 10:biomedicines10071671. [PMID: 35884976 PMCID: PMC9313426 DOI: 10.3390/biomedicines10071671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 12/03/2022] Open
Abstract
The Forkhead box protein M1 (FoxM1) is an appealing target for anti-cancer therapeutics as this cell proliferation-associated transcription factor is overexpressed in most human cancers. FoxM1 is involved in tumor invasion, angiogenesis, and metastasis. To discover novel inhibitors that disrupt the FoxM1-DNA interaction, we identified CDI, a small molecule that inhibits the FoxM1–DNA interaction. CDI was identified through an assay based on the time-resolved fluorescence energy transfer response of a labeled consensus oligonucleotide that was bound to a recombinant FoxM1-dsDNA binding domain (FoxM1-DBD) protein and exhibited potent inhibitory activity against FoxM1-DNA interaction. CDI suppressed cell proliferation and induced apoptosis in MDA-MB-231 cells obtained from a breast cancer patient. Furthermore, it decreased not only the mRNA and protein expression of FoxM1 but also that of downstream targets such as CDC25b. Additionally, global transcript profiling of MDA-MB-231 cells by RNA-Seq showed that CDI decreases the expression of FoxM1-regulated genes. The docking and MD simulation results indicated that CDI likely binds to the DNA interaction site of FoxM1-DBD and inhibits the function of FoxM1-DBD. These results of CDI being a possible effective inhibitor of FoxM1-DNA interaction will encourage its usage in pharmaceutical applications.
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28
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Ho DWH, Lam WLM, Chan LK, Ng IOL. Investigation of Functional Synergism of CENPF and FOXM1 Identifies POLD1 as Downstream Target in Hepatocellular Carcinoma. Front Med (Lausanne) 2022; 9:860395. [PMID: 35865168 PMCID: PMC9295863 DOI: 10.3389/fmed.2022.860395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 06/17/2022] [Indexed: 11/26/2022] Open
Abstract
Background Lines of evidence implicate CENPF and FOXM1 may have novel co-operative roles in driving hepatocellular carcinoma (HCC). Objective We investigated the clinicopathological correlation, functional characterization, molecular mechanism and translational significance of CENPF and FOXM1. Methods We carried out integrative studies investigating functional synergism of CENPF and FOXM1 in HCC and its metastasis. Human HCC samples, HCC cell lines and mouse model were used in the studies. Stable knockdown, q-PCR, Western blotting, whole-transcriptomic sequencing (RNA-seq), as well as cell and mouse assays were performed. Results Upon clinicopathological correlation, we found that co-overexpression of CENPF and FOXM1 in human HCCs was associated with more aggressive tumor behavior including presence of venous invasion, tumor microsatellite formation, and absence of tumor encapsulation. Moreover, co-silencing FOXM1 and CENPF using shRNA approach in HCC cell lines resulted in significantly reduced cell proliferation. Furthermore, our RNA-seq and differential gene expression analysis delineated that CENPF and FOXM1 co-regulated a specific set of target genes in various metabolic processes and oncogenic signaling pathways. Among them, POLD1, which encodes the catalytic subunit of DNA polymerase δ, was ranked as the top downstream target co-regulated by CENPF and FOXM1. POLD1 expression was positively correlated with that of FOXM1 and CENPF in HCCs. In addition, POLD1 expression was significantly upregulated in HCC tumors. Functionally, in vivo orthotopic injection model showed that stable knockdown of POLD1 in HCC cells suppressed tumor incidence and tumorigenicity and had a trend of diminished lung metastasis. Conclusion Taken together, our data suggest that CENPF and FOXM1 could synergistically support hepatocarcinogenesis via the regulation of POLD1. CENPF and FOXM1 may represent new vulnerabilities to novel drug-based therapy in HCC.
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29
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Agemura T, Hasegawa T, Yari S, Kikuta J, Ishii M. Arthritis-associated osteoclastogenic macrophage, AtoM, as a key player in pathological bone erosion. Inflamm Regen 2022; 42:17. [PMID: 35650653 PMCID: PMC9161570 DOI: 10.1186/s41232-022-00206-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/11/2022] [Indexed: 11/10/2022] Open
Abstract
Osteoclasts are myeloid lineage cells with a unique bone-destroying ability that maintains bone homeostasis together with bone formation by osteoblasts. An advanced intravital imaging system using a two-photon microscopy has enabled the observation and evaluation of osteoclast dynamics and behaviors in the bone marrow of living mice. Using this system, it has become clear that pathological osteoclasts under inflamed conditions differ from physiological osteoclasts under a steady-state. Recently, we identified novel osteoclast precursors in arthritis, called arthritis-associated osteoclastogenic macrophages (AtoMs), which differentiate into pathological osteoclasts and induce inflammatory bone destruction. In this review, we introduce the in vivo imaging of physiological and pathological osteoclasts and their differentiation mechanism.
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Affiliation(s)
- Tomoya Agemura
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Shinya Yari
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.,WPI-Immunology Frontier Research Center, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Asagi Saito, Osaka, Ibaraki, 567-0085, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. .,WPI-Immunology Frontier Research Center, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. .,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Asagi Saito, Osaka, Ibaraki, 567-0085, Japan.
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Xu T, Jiang Y, Yuan S, Zhang L, Chen X, Zhao W, Cai L, Xiao B, Jia L. Andrographolide Inhibits ER-Positive Breast Cancer Growth and Enhances Fulvestrant Efficacy via ROS-FOXM1-ER-α Axis. Front Oncol 2022; 12:899402. [PMID: 35615146 PMCID: PMC9124841 DOI: 10.3389/fonc.2022.899402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/13/2022] [Indexed: 12/02/2022] Open
Abstract
Estrogen receptor (ER)-positive breast cancer is the main subtype of breast cancer (BRCA) with high incidence and mortality. Andrographolide (AD), a major active component derived from the traditional Chinese medicine Andrographis paniculate, has substantial anti-cancer effect in various tumors. However, the antitumor efficacy and the underlying molecular mechanisms of AD on ER-positive breast cancer are poorly understood. In the present study, we demonstrated that andrographolide (AD) significantly inhibited the growth of ER-positive breast cancer cells. Mechanistically, AD suppressed estrogen receptor 1 (ESR1, encodes ER-α) transcription to inhibit tumor growth. Further studies revealed that AD induced ROS production to down-regulate FOXM1-ER-α axis. Conversely, inhibiting ROS production with N-acetylcysteine (NAC) elevated AD-decreased ER-α expression, which could be alleviated by FOXM1 knockdown. In addition, AD in combination with fulvestrant (FUL) synergistically down-regulated ER-α expression to inhibit ER-positive breast cancer both in vitro and in vivo. These findings collectively indicate that AD suppresses ESR1 transcription through ROS-FOXM1 axis to inhibit ER-positive breast cancer growth and suggest that AD might be a potential therapeutic agent and fulvestrant sensitizer for ER-positive breast cancer treatment.
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Bailly C. The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications. Eur J Pharmacol 2022; 914:174661. [PMID: 34863996 DOI: 10.1016/j.ejphar.2021.174661] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022]
Abstract
The bacterial thiopeptide thiostrepton (TS) is used as a veterinary medicine to treat bacterial infections. TS is a protein translation inhibitor, essentially active against Gram-positive bacteria and some Gram-negative bacteria. In procaryotes, TS abrogates binding of GTPase elongation factors to the 70S ribosome, by altering the structure of rRNA-L11 protein complexes. TS exerts also antimalarial effects by disrupting protein synthesis in the apicoplast genome of Plasmodium falciparum. Interestingly, the drug targets both the infectious pathogen (bacteria or parasite) and host cell, by inducing endoplasmic reticulum stress-mediated autophagy which contributes to enhance the host cell defense. In addition, TS has been characterized as a potent chemical inhibitor of the oncogenic transcription factor FoxM1, frequently overexpressed in cancers or other diseases. The capacity of TS to crosslink FoxM1, and a few other proteins such as peroxiredoxin 3 (PRX3) and the 19S proteasome, contributes to the anticancer effects of the thiopeptide. The anticancer activities of TS evidenced using diverse tumor cell lines, in vivo models and drug combinations are reviewed here, together with the implicated targets and mechanisms. The difficulty to formulate TS is a drag on the pharmaceutical development of the natural product. However, the design of hemisynthetic analogues and the use of micellar drug delivery systems should facilitate a broader utilization of the compound in human and veterinary medicines. This review shed light on the many pharmacological properties of TS, with the objective to promote its use as a pharmacological tool and medicinal product.
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Affiliation(s)
- Christian Bailly
- OncoWitan, Scientific Consulting Office, Lille, Wasquehal, 59290, France.
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Hosoya T, Saito T, Baba H, Tanaka N, Noda S, Komiya Y, Tagawa Y, Yamamoto A, Mizoguchi F, Kawahata K, Miyasaka N, Kohsaka H, Yasuda S. Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts. Rheumatology (Oxford) 2021; 61:3427-3438. [PMID: 34849618 PMCID: PMC9348617 DOI: 10.1093/rheumatology/keab874] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/13/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for rheumatoid arthritis (RA) via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. METHODS CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA, and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. RESULTS CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction, and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. CONCLUSION The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Since the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects.
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Affiliation(s)
- Tadashi Hosoya
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuya Saito
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiroyuki Baba
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nao Tanaka
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Seiji Noda
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Youji Komiya
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yasuhiro Tagawa
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Akio Yamamoto
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Fumitaka Mizoguchi
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kimito Kawahata
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nobuyuki Miyasaka
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hitoshi Kohsaka
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shinsuke Yasuda
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Structure-based virtual screening towards the discovery of novel FOXM1 inhibitors. Future Med Chem 2021; 14:207-219. [PMID: 34809496 DOI: 10.4155/fmc-2021-0282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design (CADD). We selected XST-119 through virtual screening, performed surface plasmon resonance and in vitro cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mouse model. Conclusion: We identified XST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.
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Agemura T, Hasegawa T, Yari S, Kikuta J, Ishii M. Arthritis-associated osteoclastogenic macrophages (AtoMs) participate in pathological bone erosion in rheumatoid arthritis. Immunol Med 2021; 45:22-26. [PMID: 34187325 DOI: 10.1080/25785826.2021.1944547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Rheumatoid arthritis is a chronic form of arthritis that causes bone destruction in joints such as the knees and fingers. Over the past two decades, the clinical outcomes of rheumatoid arthritis have improved substantially with the development of biological agents and Janus kinase inhibitors. Osteoclasts are myeloid lineage cells with a unique bone-destroying ability that can lead to joint destruction. On the other hand, osteoclasts play an important role in skeletal homeostasis by supporting bone remodeling together with osteoblasts in the bone marrow under steady-state conditions. However, the same osteoclasts are considered to participate in physiological bone remodeling and joint destruction. We found that pathological osteoclasts have different differentiation pathways and regulatory transcription factors compared to physiological osteoclasts. We also identified arthritis-associated osteoclastogenic macrophages (AtoMs), which are common progenitors of pathological osteoclasts in mice and humans that develop specifically in inflamed synovial tissue. This review presents details of the newly identified AtoMs and the original intravital imaging systems that can visualize synovial tissue and pathological osteoclasts at the pannus-bone interface.
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Affiliation(s)
- Tomoya Agemura
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan
| | - Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan
| | - Shinya Yari
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Suita, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Suita, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
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Ulhaka K, Kanokwiroon K, Khongkow M, Bissanum R, Khunpitak T, Khongkow P. The Anticancer Effects of FDI-6, a FOXM1 Inhibitor, on Triple Negative Breast Cancer. Int J Mol Sci 2021; 22:6685. [PMID: 34206484 PMCID: PMC8269391 DOI: 10.3390/ijms22136685] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 01/06/2023] Open
Abstract
Triple-negative breast cancer (TNBC) presents an important clinical challenge, as it does not respond to endocrine therapies or other available targeting agents. FOXM1, an oncogenic transcriptional factor, has reported to be upregulated and associated with poor clinical outcomes in TNBC patients. In this study, we investigated the anti-cancer effects of FDI-6, a FOXM1 inhibitor, as well as its molecular mechanisms, in TNBC cells. Two TNBC cell lines, MDA-MB-231 and HS578T, were used in this study. The anti-cancer activities of FDI-6 were evaluated using various 2D cell culture assays, including Sulforhodamine B (SRB), wound healing, and transwell invasion assays together with 3D spheroid assays, mimicking real tumour structural properties. After treatment with FDI-6, the TNBC cells displayed a significant inhibition in cell proliferation, migration, and invasion. Increased apoptosis was also observed in the treated cells. In addition, we found that FDI-6 lead to the downregulation of FOXM1 and its key oncogenic targets, including CyclinB1, Snail, and Slug. Interestingly, we also found that the FDI-6/Doxorubicin combination significantly enhanced the cytotoxicity and apoptotic properties, suggesting that FDI-6 might improve chemotherapy treatment efficacy and reduce unwanted side effects. Altogether, FDI-6 exhibited promising anti-tumour activities and could be developed as a newly effective treatment for TNBC.
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Affiliation(s)
- Karan Ulhaka
- Institute of Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.U.); (T.K.)
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.K.); (R.B.)
| | - Kanyanatt Kanokwiroon
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.K.); (R.B.)
| | - Mattaka Khongkow
- National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathumthani 12120, Thailand;
| | - Rassanee Bissanum
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.K.); (R.B.)
| | - Thanaporn Khunpitak
- Institute of Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.U.); (T.K.)
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.K.); (R.B.)
| | - Pasarat Khongkow
- Institute of Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.U.); (T.K.)
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; (K.K.); (R.B.)
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
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Sun X, Luo Z, Gong L, Tan X, Chen J, Liang X, Cai M. Identification of significant genes and therapeutic agents for breast cancer by integrated genomics. Bioengineered 2021; 12:2140-2154. [PMID: 34151730 PMCID: PMC8806825 DOI: 10.1080/21655979.2021.1931642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Breast cancer is the most commonly diagnosed malignancy in women; thus, more cancer prevention research is urgently needed. The aim of this study was to predict potential therapeutic agents for breast cancer and determine their molecular mechanisms using integrated bioinformatics. Summary data from a large genome-wide association study of breast cancer was derived from the UK Biobank. The gene expression profile of breast cancer was from the Oncomine database. We performed a network-wide association study and gene set enrichment analysis to identify the significant genes in breast cancer. Then, we performed Gene Ontology analysis using the STRING database and conducted Kyoto Encyclopedia of Genes and Genomes pathway analysis using Cytoscape software. We verified our results using the Gene Expression Profile Interactive Analysis, PROgeneV2, and Human Protein Atlas databases. Connectivity map analysis was used to identify small-molecule compounds that are potential therapeutic agents for breast cancer. We identified 10 significant genes in breast cancer based on the gene expression profile and genome-wide association study. A total of 65 small-molecule compounds were found to be potential therapeutic agents for breast cancer.
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Affiliation(s)
- Xiao Sun
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Zhenzhen Luo
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Liuyun Gong
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Xinyue Tan
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Jie Chen
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Xin Liang
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Mengjiao Cai
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
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Liu C, Barger CJ, Karpf AR. FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer. Cancers (Basel) 2021; 13:3065. [PMID: 34205406 PMCID: PMC8235333 DOI: 10.3390/cancers13123065] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.
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Affiliation(s)
| | | | - Adam R. Karpf
- Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68918-6805, USA; (C.L.); (C.J.B.)
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Godwin I, Anto NP, Bava SV, Babu MS, Jinesh GG. Targeting K-Ras and apoptosis-driven cellular transformation in cancer. Cell Death Discov 2021; 7:80. [PMID: 33854056 PMCID: PMC8047025 DOI: 10.1038/s41420-021-00457-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/23/2021] [Accepted: 03/21/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.
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Affiliation(s)
- Isha Godwin
- Saveetha Medical College, Thandalam, Chennai, Tamil Nadu, 602105, India.
| | - Nikhil Ponnoor Anto
- Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Smitha V Bava
- Department of Biotechnology, University of Calicut, Malappuram, Kerala, 673635, India
| | - Mani Shankar Babu
- Department of Botany, University College, Thiruvananthapuram, Kerala, 695 034, India
| | - Goodwin G Jinesh
- Departments of Molecular Oncology, and Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
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Huang F, Teng K, Liu Y, Cao Y, Wang T, Ma C, Zhang J, Zhong J. Bacteriocins: Potential for Human Health. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5518825. [PMID: 33936381 PMCID: PMC8055394 DOI: 10.1155/2021/5518825] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 11/17/2022]
Abstract
Due to the challenges of antibiotic resistance to global health, bacteriocins as antimicrobial compounds have received more and more attention. Bacteriocins are biosynthesized by various microbes and are predominantly used as food preservatives to control foodborne pathogens. Now, increasing researches have focused on bacteriocins as potential clinical antimicrobials or immune-modulating agents to fight against the global threat to human health. Given the broad- or narrow-spectrum antimicrobial activity, bacteriocins have been reported to inhibit a wide range of clinically pathogenic and multidrug-resistant bacteria, thus preventing the infections caused by these bacteria in the human body. Otherwise, some bacteriocins also show anticancer, anti-inflammatory, and immune-modulatory activities. Because of the safety and being not easy to cause drug resistance, some bacteriocins appear to have better efficacy and application prospects than existing therapeutic agents do. In this review, we highlight the potential therapeutic activities of bacteriocins and suggest opportunities for their application.
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Affiliation(s)
- Fuqing Huang
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Kunling Teng
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yayong Liu
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Yanhong Cao
- The Animal Husbandry Research Institute of Guangxi Zhuang Autonomous Region, Nanning 530000, China
| | - Tianwei Wang
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Cui Ma
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jie Zhang
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jin Zhong
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100008, China
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FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo. Cancers (Basel) 2021; 13:cancers13050956. [PMID: 33668819 PMCID: PMC7956612 DOI: 10.3390/cancers13050956] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/03/2021] [Accepted: 02/22/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Late diagnosis of ovarian cancer is a major reason for the high mortality rate of this tumor entity. The time to determine tumor susceptibility to treatment is scarce and resistance to therapy occurs very frequently. Here, we aim for a model system that can determine tumor response to (I) study novel drugs and (II) enhance patient stratification. Tissue specimens (n = 10) were acquired from fresh surgical samples. Tissue cultures were cultivated and treated with clinically relevant therapeutics and an FOXM1 inhibitor for 3–6 days. The transcription factor FOXM1 is a key regulator of tumor survival affecting multiple cancerogenic target genes. Gene expression of FOXM1 and its targets BRCA1/2 and RAD51 were investigated together with tumor susceptibility. Tissue cultures successfully demonstrated the individual benefit of FOXM1 inhibition and revealed the potency of the complex model system for oncological research. Abstract Diagnosis in an advanced state is a major hallmark of ovarian cancer and recurrence after first line treatment is common. With upcoming novel therapies, tumor markers that support patient stratification are urgently needed to prevent ineffective therapy. Therefore, the transcription factor FOXM1 is a promising target in ovarian cancer as it is frequently overexpressed and associated with poor prognosis. In this study, fresh tissue specimens of 10 ovarian cancers were collected to investigate tissue cultures in their ability to predict individual treatment susceptibility and to identify the benefit of FOXM1 inhibition. FOXM1 inhibition was induced by thiostrepton (3 µM). Carboplatin (0.2, 2 and 20 µM) and olaparib (10 µM) were applied and tumor susceptibility was analyzed by tumor cell proliferation and apoptosis in immunofluorescence microscopy. Resistance mechanisms were investigated by determining the gene expression of FOXM1 and its targets BRCA1/2 and RAD51. Ovarian cancer tissue was successfully maintained for up to 14 days ex vivo, preserving morphological characteristics of the native specimen. Thiostrepton downregulated FOXM1 expression in tissue culture. Individual responses were observed after combined treatment with carboplatin or olaparib. Thus, we successfully implemented a complex tissue culture model to ovarian cancer and showed potential benefit of combined FOXM1 inhibition.
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Wongkhieo S, Numdee K, Lam EWF, Choowongkomon K, Kongsema M, Khongkow M. Liposomal Thiostrepton Formulation and Its Effect on Breast Cancer Growth Inhibition. J Pharm Sci 2021; 110:2508-2516. [PMID: 33515584 DOI: 10.1016/j.xphs.2021.01.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/30/2022]
Abstract
Forkhead box M1 (FOXM1) is known to play a role in breast cancer progression. FOXM1 inhibition becomes one of the strategies in developing the novel cancer therapy. Recently, thiostrepton has been recognized as a potent FOXM1 inhibitor. To improve its potential, we aimed to develop a nanodelivery system for thiostrepton. Here, liposome-encapsulated thiostrepton (TSLP) was developed. Physiochemical properties were characterized by TEM and dynamic light scattering technique. The biological activities were also evaluated, by cellular internalization, MTT assay, spheroid formation assay and RT-PCR. The result showed that the range sizes of TSLP were 152 ± 2 nm, polydispersity index (PdI) of 0.23 ± 0.02 and zeta potential of -20.2 ± 0.1 mV. As expected, TSLP showed a higher potential in reducing FOXM1 levels in MCF-7 cells than free thiostrepton. Additionally, TSLP significantly improved the efficiently and specificity of thiostrepton in reducing cell viability of MCF-7, but not of the fibroblast (HDFn) cells. Interestingly, TSLP had an ability to induce MCF-7 cell death in both 2D monolayer and 3D spheroid culture. In conclusions, TSLP could possibly be one of the potential developments using nano-delivery system to improve abilities and specificity of thiostrepton in breast cancer cell inhibition and death inducing, with decreasing non-specific toxicity.
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Affiliation(s)
- Sudtirak Wongkhieo
- Department of Zoology, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand; National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand
| | - Katawut Numdee
- National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand
| | - Eric W F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
| | - Mesayamas Kongsema
- Department of Zoology, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
| | - Mattaka Khongkow
- National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
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Mosca L, Ilari A, Fazi F, Assaraf YG, Colotti G. Taxanes in cancer treatment: Activity, chemoresistance and its overcoming. Drug Resist Updat 2021; 54:100742. [PMID: 33429249 DOI: 10.1016/j.drup.2020.100742] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Since 1984, when paclitaxel was approved by the FDA for the treatment of advanced ovarian carcinoma, taxanes have been widely used as microtubule-targeting antitumor agents. However, their historic classification as antimitotics does not describe all their functions. Indeed, taxanes act in a complex manner, altering multiple cellular oncogenic processes including mitosis, angiogenesis, apoptosis, inflammatory response, and ROS production. On the one hand, identification of the diverse effects of taxanes on oncogenic signaling pathways provides opportunities to apply these cytotoxic drugs in a more rational manner. On the other hand, this may facilitate the development of novel treatment modalities to surmount anticancer drug resistance. In the latter respect, chemoresistance remains a major impediment which limits the efficacy of antitumor chemotherapy. Taxanes have shown impact on key molecular mechanisms including disruption of mitotic spindle, mitosis slippage and inhibition of angiogenesis. Furthermore, there is an emerging contribution of cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation to the acquisition of taxane resistance. Hence, these two lines of findings are currently promoting a more rational and efficacious taxane application as well as development of novel molecular strategies to enhance the efficacy of taxane-based cancer treatment while overcoming drug resistance. This review provides a general and comprehensive picture on the use of taxanes in cancer treatment. In particular, we describe the history of application of taxanes in anticancer therapeutics, the synthesis of the different drugs belonging to this class of cytotoxic compounds, their features and the differences between them. We further dissect the molecular mechanisms of action of taxanes and the molecular basis underlying the onset of taxane resistance. We further delineate the possible modalities to overcome chemoresistance to taxanes, such as increasing drug solubility, delivery and pharmacokinetics, overcoming microtubule alterations or mitotic slippage, inhibiting drug efflux pumps or drug metabolism, targeting redox metabolism, immune response, and other cellular functions.
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Affiliation(s)
- Luciana Mosca
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
| | - Francesco Fazi
- Dept. Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University, Via A. Scarpa 14-16, 00161 Rome, Italy
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
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Shibui Y, Kohashi K, Tamaki A, Kinoshita I, Yamada Y, Yamamoto H, Taguchi T, Oda Y. The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor. J Cancer Res Clin Oncol 2020; 147:1499-1518. [PMID: 33221995 DOI: 10.1007/s00432-020-03438-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/22/2020] [Indexed: 12/20/2022]
Abstract
PURPOSE Malignant rhabdoid tumor (MRT) is a rare, highly aggressive sarcoma with an uncertain cell of origin. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is very poor. Novel antitumor agents are needed for MRT patients. Forkhead box transcription factor 1 (FOXM1) is overexpressed and is correlated with the pathogenesis in several human malignancies. In this study, we identified the clinicopathological and prognostic values of the expression of FOXM1 and its roles in the progression of MRT. METHODS We investigated the FOXM1 expression levels and their clinical significance in 23 MRT specimens using immunohistochemistry and performed clinicopathologic and prognostic analyses. We also demonstrated correlations between the downregulation of FOXM1 and oncological characteristics using small interfering RNA (siRNA) and FOXM1 inhibitor in MRT cell lines. RESULTS Histopathological analyses revealed that primary renal MRTs showed significantly low FOXM1 protein expression levels (p = 0.032); however, there were no significant differences in other clinicopathological characteristics or the survival rate. FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to chemotherapeutic agents, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines. A cDNA microarray analysis showed that FOXM1 regulated FANCD2 and NBS1, which are key genes for DNA damage repair. CONCLUSION This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT.
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Affiliation(s)
- Yuichi Shibui
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Akihiko Tamaki
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Izumi Kinoshita
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuichi Yamada
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
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Cai X, Xiao W, Shen J, Lian H, Lu Y, Liu X, Gu J. Thiostrepton and miR-216b synergistically promote osteosarcoma cell cytotoxicity and apoptosis by targeting FoxM1. Oncol Lett 2020; 20:391. [PMID: 33193851 PMCID: PMC7656114 DOI: 10.3892/ol.2020.12254] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 09/07/2020] [Indexed: 01/08/2023] Open
Abstract
Osteosarcoma is a common primary bone cancer that there are currently no effective treatment strategies for. Forkhead box M1 (FoxM1) is key in the development of osteosarcoma, and microRNA (miR)-216b serves an antitumor role by targeting FoxM1. Moreover, thiostrepton (TST), a natural thiazole antibiotic, induces antitumor effects and specifically targets FoxM1. Therefore, the present study investigated whether thiostrepton and miR-216b synergistically inhibited osteosarcoma cells by targeting FoxM1. The MTT assay, reverse transcription-quantitative PCR, a dual-luciferase reporter assay and flow cytometry were performed. Compared with the human osteoblast cell line hFOB1.19, miR-216b expression was significantly downregulated in the osteosarcoma cell lines U2OS, MG63 and Saos-2. By contrast, FoxM1 expression was significantly upregulated in osteosarcoma cell lines compared with the hFOB1.19 cell line. The results indicated that miR-216b targeted the 3′-untranslated region of FoxM1. Moreover, the results suggested that miR-216b cooperated with TST to decrease cell cytotoxicity and increase cell apoptosis. In addition, miR-216b cooperated with TST to increase Bax expression and decrease Bcl-2 expression. In conclusion, the combination of TST and miR-216b synergistically promoted osteosarcoma cell cytotoxicity and apoptosis by targeting FoxM1. Therefore, the present study suggested that the combination of TST and miR-216b may serve as a promising therapeutic strategy for osteosarcoma.
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Affiliation(s)
- Xiaobing Cai
- Department of Orthopedics, Chongming Branch of Tongji Univercity Affiliated the Tenth People's Hospital, Shanghai 202157, P.R. China
| | - Wenyu Xiao
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Juexin Shen
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Hui Lian
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Yi Lu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Xianmiao Liu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Jisheng Gu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
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Kase AM, Copland III JA, Tan W. Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer. Onco Targets Ther 2020; 13:10499-10513. [PMID: 33116629 PMCID: PMC7576355 DOI: 10.2147/ott.s266085] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.
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Affiliation(s)
- Adam M Kase
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
| | - John A Copland III
- Mayo Clinic Florida Department of Cancer Biology, Jacksonville, FL32224, USA
| | - Winston Tan
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
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Zhu X, Lu K, Cao L, Hu Y, Yin Y, Cai Y. FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion. Cancer Manag Res 2020; 12:9857-9867. [PMID: 33116844 PMCID: PMC7555408 DOI: 10.2147/cmar.s270825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
Background Osteosarcoma (OS) is a highly aggressive bone malignancy that is mostly diagnosed in children and young adults. Increasing evidence indicates that the transcription factor Forkhead Box M1 (FoxM1) plays a key role in the pathogenesis of various tumors. However, the function of FoxM1 in OS has not been clearly elucidated. Methods In the present study, we first analyzed the expressions of FoxM1 in human OS and myositis ossificans (MO, included as a control) tissues by immunohistochemistry. To investigate the functional significance of FoxM1 in OS tumorigenesis, we examined the effects of FoxM1 downregulation in MG-63 and HOS-MNNG cells by either short hairpin RNA (shRNA)-mediated gene silencing or treatment with thiostrepton, a specific FoxM1 inhibitor. Results FoxM1 was detected in 82.1% (55/67) of OS vs only 10% (2/20) of MO samples. High expressions of FoxM1 were also detected in three human OS cell lines (HOS-MNNG, MG-63, and U-2OS). FoxM1 downregulation significantly reduced MG-63 and HOS-MNNG cell proliferation, migration, and invasion as well as cell cycle arrest in the G2/M phase and increased apoptotic cell death. Conclusion The present study demonstrated the critical role of FoxM1 in the pathogenesis of OS. Therefore, FoxM1 may serve as a potential therapeutic target for the treatment of OS.
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Affiliation(s)
- Xia Zhu
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei 230032, People's Republic of China.,Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Kangyang Lu
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei 230032, People's Republic of China
| | - Liyu Cao
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei 230032, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Yong Hu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Yu Yin
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei 230032, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Yongping Cai
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei 230032, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
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Zhang Z, Tu K, Liu F, Liang M, Yu K, Wang Y, Luo Y, Yang B, Qin Y, He D, Jiang G, Huang O, Zou Y. FoxM1 promotes the migration of ovarian cancer cell through KRT5 and KRT7. Gene 2020; 757:144947. [PMID: 32659254 DOI: 10.1016/j.gene.2020.144947] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/30/2020] [Accepted: 07/06/2020] [Indexed: 12/28/2022]
Abstract
Forkhead box M1(FoxM1) played an important role in the pathogenesis of ovarian cancer, but its downstream molecular network is mysterious. Here, we combined ChIP-seq with RNA-seq analysis and identified 687 FoxM1-binding regions and 182 genes regulated by FoxM1. The above data pointed out that KRT5 and KRT7 were downstream target genes of FoxM1. Next, we used qPCR and Western blot to verify that FoxM1 knockdown inhibited the expression levels of KRT5 and KRT7. We also demonstrated that FoxM1 regulated KRT5 and KRT7 genes expression through binding a consensus AP-2 cis element, and showed that KRT5 and KRT7 deficiency could prevent the migration but not proliferation of SK-OV-3 cells. Finally, tissue microarray results indicated that KRT5 and KRT7 were highly expressed in ovarian cancer and positively correlated with FoxM1 expression. TCGA database showed that high expression of KRT5 and KRT7 could significantly reduce the survival rate of patients with ovarian cancer. The above results clarify the specific downstream molecular network of FoxM1 to promote the pathogenesis of ovarian cancer, and provide a basis experiment for the judgment of ovarian cancer prognosis and the design of drug targets.
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Affiliation(s)
- Ziyu Zhang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Kaijia Tu
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Faying Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Meirong Liang
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Kaihui Yu
- The College of Medicine, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yaoqing Wang
- The College of Medicine, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yong Luo
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Bicheng Yang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Yunna Qin
- Department of Pathology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Deming He
- Department of Pathology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Guoyi Jiang
- Department of Obstetrics, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, 330006, PR China
| | - Ouping Huang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China.
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China; Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, PR China.
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Ghandhariyoun N, Jaafari MR, Nikoofal-Sahlabadi S, Taghdisi SM, Moosavian SA. Reducing Doxorubicin resistance in breast cancer by liposomal FOXM1 aptamer: In vitro and in vivo. Life Sci 2020; 262:118520. [PMID: 33010284 DOI: 10.1016/j.lfs.2020.118520] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/14/2022]
Abstract
AIMS Drug resistance is one of the main obstacles in cancer chemotherapy. The forkhead box M1 (FOXM1) is a transcription factor and its overexpression in breast cancer is related to resistance to chemotherapy. In this study, we prepare liposomal FOXM1 aptamer (Lip-FOXM1apt) and evaluate its effects on Doxorubicin (Dox) resistance in vitro and in vivo. MAIN METHODS MTT assay, cell association, cellular uptake, Annexin V-FITC/PI dual staining assay were investigated in MDA-MB-231, MCF-7, 4T1. In vivo studies were performed in 4T1 tumor-bearing BALB/c mice. KEY FINDINGS We found that the combination therapy of Dox and Lip-FOXM1apt significantly increases both Dox cytotoxicity on cancer cells as well as Dox-induced apoptosis. Administering Lip-FOXM1apt remarkably improved the anti-tumor efficacy of Dox in mice model that was strikingly more effective than Dox monotherapy. SIGNIFICANCE Taken together, this study provides a new strategy to overcome Dox resistance and merits further investigation.
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Affiliation(s)
- Negin Ghandhariyoun
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran
| | - Sara Nikoofal-Sahlabadi
- Department of Pharmaceutics, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Seyed Mohammad Taghdisi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Alia Moosavian
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran.
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Dey P, Wang A, Ziegler Y, Kim SH, El-Ashry D, Katzenellenbogen JA, Katzenellenbogen BS. Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer. Cancers (Basel) 2020; 12:cancers12092677. [PMID: 32961773 PMCID: PMC7565743 DOI: 10.3390/cancers12092677] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Triple negative breast cancer is an aggressive subtype of breast cancer that frequently metastasizes. Because the transcription factor FOXM1 is highly upregulated in triple negative breast cancer and controls many cell activities that lead to cancer progression and metastasis, we sought to determine if FOXM1 inhibitory compounds could effectively suppress the invasiveness and progression of triple negative breast cancer cells and tumors. Our findings show that these compounds inhibit cell motility, invasiveness, and the expression of important proteins associated with epithelial to mesenchymal transition. These compounds also suppressed the proliferation and metastatic outgrowth of triple negative breast tumors. Thus, these findings highlight the crucial role of FOXM1 in promoting the progression and metastasis of these cancers, and suggest that FOXM1 inhibitory compounds may have therapeutic potential and prove beneficial in intervention against triple negative breast cancer. Abstract Metastasis-related complications account for the overwhelming majority of breast cancer mortalities. Triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, has a high propensity to metastasize to distant organs, leading to poor patient survival. The forkhead transcription factor, FOXM1, is especially upregulated and overexpressed in TNBC and is known to regulate multiple signaling pathways that control many key cancer properties, including proliferation, invasiveness, stem cell renewal, and therapy resistance, making FOXM1 a critical therapeutic target for TNBC. In this study, we test the effectiveness of a novel class of 1,1-diarylethylene FOXM1 inhibitory compounds in suppressing TNBC cell migration, invasion, and metastasis using in vitro cell culture and in vivo tumor models. We show that these compounds inhibit the motility and invasiveness of TNBC MDA-MB-231 and DT28 cells, along with reducing the expression of important epithelial to mesenchymal transition (EMT) associated genes. Further, orthotopic tumor studies in NOD-SCID-gamma (NSG) mice demonstrate that these compounds reduce FOXM1 expression and suppress TNBC tumor growth as well as distant metastasis. Gene expression and protein analyses confirm the decreased levels of EMT factors and FOXM1-regulated target genes in tumors and metastatic lesions in the inhibitor-treated animals. The findings suggest that these FOXM1 suppressive compounds may have therapeutic potential in treating triple negative breast cancer, with the aim of reducing tumor progression and metastatic outgrowth.
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Affiliation(s)
- Parama Dey
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (P.D.); (A.W.); (Y.Z.)
| | - Alexander Wang
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (P.D.); (A.W.); (Y.Z.)
| | - Yvonne Ziegler
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (P.D.); (A.W.); (Y.Z.)
| | - Sung Hoon Kim
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (S.H.K.); (J.A.K.)
| | - Dorraya El-Ashry
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA;
| | - John A. Katzenellenbogen
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (S.H.K.); (J.A.K.)
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Benita S. Katzenellenbogen
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (P.D.); (A.W.); (Y.Z.)
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence: ; Tel.: +1-217-333-9769
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Alasiri G, Jiramongkol Y, Trakansuebkul S, Ke HL, Mahmud Z, Intuyod K, Lam EWF. Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival. Mol Cell Endocrinol 2020; 515:110932. [PMID: 32615282 PMCID: PMC7493713 DOI: 10.1016/j.mce.2020.110932] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 01/06/2023]
Abstract
Pharmaceutical inhibitors of the endoplasmic reticulum (ER)-stress modulator PERK (eIF2AK3) have demonstrated anticancer activities in combination therapies, but their effectiveness as a single agent is limited, suggesting the existence of possible compensatory cellular responses. To explore the potential mechanisms involved, we performed time-course drug treatment experiments on the parental MCF-7 and drug resistant MCF-7EpiR and MCF-7TaxR breast cancer cells and identified GCN2 (eIF2AK4) as a molecule that can potentially cooperate with PERK to regulate FOXO3 via JNK and AKT to modulate drug response. Consistently, GCN2 knockdown severely impaired the clonal survival of parental and resistant MCF-7 cells and sensitised them to epirubicin and paclitaxel treatment. Western blot, RT-qPCR and ChIP analyses also confirmed that GCN2 inactivation causes an induction of JNK and thereby FOXO3 activity, culminating in an increase in PERK activity and expression at the transcription level. Conversely, PERK-inactivation using GSK2606414-induces an induction in GCN2 expression and activity also associated with JNK. In agreement, we also showed that the perk-/- MEFs, expressing elevated levels of P-JNK, JNK, GCN2 and reduced levels of P-AKT and P-FOXO3, have lower clonogenicity and are more sensitive to epirubicin compared to wild-type MEFs. Similarly, gcn2-/- MEFs expressing augmented levels of P-JNK, JNK, P-PERK, PERK and lower levels of P-AKT and P-FOXO3 also had lower clonogenicity and were more sensitive to epirubicin and PERK-inhibition. In addition, JNK1/2 deletion in MEFs resulted in reduced levels of GCN2, FOXO3, PERK, P-PERK expression as well as FOXO3 activity and enhanced clonal survival and resistance to PERK-inhibition. Together these results demonstrate that GCN2 cooperates with PERK through the JNK-FOXO3 axis in a reciprocal negative feedback loop to mediate cancer chemotherapeutic drug response and clonal survival, advocating the potential of targeting GCN2 as a therapeutic strategy for treating cancer and for overcoming drug resistance.
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Affiliation(s)
- Glowi Alasiri
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Sasanan Trakansuebkul
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Hui-Ling Ke
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Zimam Mahmud
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Kitti Intuyod
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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