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1
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Alhammadi SHA, Baby B, Antony P, Jobe A, Humaid RSM, Alhammadi FJA, Vijayan R. Modeling the Binding of Anticancer Peptides and Mcl-1. Int J Mol Sci 2024; 25:6529. [PMID: 38928234 PMCID: PMC11203456 DOI: 10.3390/ijms25126529] [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: 03/29/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Mcl-1 (myeloid cell leukemia 1), a member of the Bcl-2 family, is upregulated in various types of cancer. Peptides representing the BH3 (Bcl-2 homology 3) region of pro-apoptotic proteins have been demonstrated to bind the hydrophobic groove of anti-apoptotic Mcl-1, and this interaction is responsible for regulating apoptosis. Structural studies have shown that, while there is high overall structural conservation among the anti-apoptotic Bcl-2 (B-cell lymphoma 2) proteins, differences in the surface groove of these proteins facilitates binding specificity. This binding specificity is crucial for the mechanism of action of the Bcl-2 family in regulating apoptosis. Bim-based peptides bind specifically to the hydrophobic groove of Mcl-1, emphasizing the importance of these interactions in the regulation of cell death. Molecular docking was performed with BH3-like peptides derived from Bim to identify high affinity peptides that bind to Mcl-1 and to understand the molecular mechanism of their interactions. The interactions of three identified peptides, E2gY, E2gI, and XXA1_F3dI, were further evaluated using 250 ns molecular dynamics simulations. Conserved hydrophobic residues of the peptides play an important role in their binding and the structural stability of the complexes. Understanding the molecular basis of interaction of these peptides will assist in the development of more effective Mcl-1 specific inhibitors.
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Affiliation(s)
- Shamsa Husain Ahmed Alhammadi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bincy Baby
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Priya Antony
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Amie Jobe
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Raghad Salman Mohammed Humaid
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Fatema Jumaa Ahmed Alhammadi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- The Big Data Analytics Center, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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2
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Wang J, He Y, Yang C, Luo Q, Wang B. Myeloid cell leukemia-1 as a candidate prognostic biomarker in cancers: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2023; 23:1017-1027. [PMID: 37467344 DOI: 10.1080/14737140.2023.2238900] [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: 05/15/2023] [Revised: 07/14/2023] [Accepted: 07/15/2023] [Indexed: 07/21/2023]
Abstract
INTRODUCTION Studies have shown that myeloma cell leukemia-1 (MCL-1) is associated with the prognosis of patients with cancer. To further validate the prognostic value of MCL-1 in cancer, a meta-analysis was conducted. METHODS Six databases were searched using Boolean logic search formulas. Data were extracted from the included literature, and pooled odds ratio, hazard ratio, and 95% confidence interval were calculated to determine the relationship between MCL-1 levels and clinicopathological characteristics and prognosis of patients with cancer. When heterogeneity was found to be significant, a random effects model was used, otherwise, a fixed effects model was used. RESULTS Twelve articles were included in this meta-analysis, totaling 2208 patients with cancer across 14 studies. A high MCL-1 expression level was associated with patients with high T stage, M stage, and TNM stage in some cancers. Additionally, high MCL-1 expression was likely to be observed in patients with poorly differentiated digestive system tumors and patients with lung adenocarcinoma. Notably, a higher expression of MCL-1 was found to be associated with shorter overall survival in patients with hematological tumors, digestive system tumors, and lung cancer. CONCLUSION MCL-1 may be a prognostic biomarker in patients with some types of cancer.
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Affiliation(s)
- Jianrong Wang
- Department of Respiratory and Critical Care Medicine, Ya'an People's Hospital, Ya'an, Sichuan, China
| | - Yu He
- Department of Respiratory and Critical Care Medicine, Ya'an People's Hospital, Ya'an, Sichuan, China
| | - Chao Yang
- Department of Respiratory and Critical Care Medicine, Ya'an People's Hospital, Ya'an, Sichuan, China
| | - Qiurui Luo
- Department of Respiratory and Critical Care Medicine, Ya'an People's Hospital, Ya'an, Sichuan, China
| | - Bingchi Wang
- Department of Respiratory and Critical Care Medicine, Ya'an People's Hospital, Ya'an, Sichuan, China
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3
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Zhao YX, Yang Z, Ma LB, Dang JY, Wang HY. Synchronous gastric cancer complicated with chronic myeloid leukemia (multiple primary cancers): A case report. World J Clin Cases 2022; 10:11146-11154. [PMID: 36338220 PMCID: PMC9631137 DOI: 10.12998/wjcc.v10.i30.11146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/09/2022] [Accepted: 09/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND With the advancement of medical technology and improvement in living standards, the incidence of multiple primary cancers has gradually increased. In particular, tumors of the digestive system account for a large proportion of multiple primary cancers. The diagnosis and treatment of chronic myeloid leukemia, particularly with synchronous gastric cancer, at the first consultation is relatively rare.
CASE SUMMARY Herein, we present the case of a middle-aged man who was referred to the Department of Hematology owing to an elevated white blood cell count. After the examination, he was diagnosed with chronic myeloid leukemia and was administered imatinib. Three months after the initial diagnosis, he visited our hospital again for abdominal pain, and further examination revealed gastric malignancy. After discussion with a multidisciplinary team, S-1 (Tegafur, Gimeracil, and Oteracil Potassium Capsules) combined with oxaliplatin—SOX regimen—was initiated. Later, the patient’s condition rapidly progressed. He developed colonic obstruction and underwent an ostomy; however, he died less than 6 months after the initial diagnosis.
CONCLUSION Multiple primary cancers are influenced by environmental and genetic factors; a standardized multidisciplinary discussion plays a key role in treatment.
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Affiliation(s)
- Yong-Xun Zhao
- The Seventh Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ze Yang
- The Seventh Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Li-Bin Ma
- The Seventh Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jia-Yao Dang
- The First Clinical Medical School, The First Clinical Medical School of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Hui-Ying Wang
- The First Clinical Medical School, The First Clinical Medical School of Lanzhou University, Lanzhou 730000, Gansu Province, China
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4
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Sancho M, Leiva D, Lucendo E, Orzáez M. Understanding MCL1: from cellular function and regulation to pharmacological inhibition. FEBS J 2022; 289:6209-6234. [PMID: 34310025 PMCID: PMC9787394 DOI: 10.1111/febs.16136] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/09/2021] [Accepted: 07/22/2021] [Indexed: 12/30/2022]
Abstract
Myeloid cell leukemia-1 (MCL1), an antiapoptotic member of the BCL2 family characterized by a short half-life, functions as a rapid sensor that regulates cell death and other relevant processes that include cell cycle progression and mitochondrial homeostasis. In cancer, MCL1 overexpression contributes to cell survival and resistance to diverse chemotherapeutic agents; for this reason, several MCL1 inhibitors are currently under preclinical and clinical development for cancer treatment. However, the nonapoptotic functions of MCL1 may influence their therapeutic potential. Overall, the complexity of MCL1 regulation and function represent challenges to the clinical application of MCL1 inhibitors. We now summarize the current knowledge regarding MCL1 structure, regulation, and function that could impact the clinical success of MCL1 inhibitors.
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Affiliation(s)
- Mónica Sancho
- Targeted Therapies on Cancer and Inflammation LaboratoryCentro de Investigación Príncipe FelipeValenciaSpain
| | - Diego Leiva
- Targeted Therapies on Cancer and Inflammation LaboratoryCentro de Investigación Príncipe FelipeValenciaSpain
| | - Estefanía Lucendo
- Targeted Therapies on Cancer and Inflammation LaboratoryCentro de Investigación Príncipe FelipeValenciaSpain
| | - Mar Orzáez
- Targeted Therapies on Cancer and Inflammation LaboratoryCentro de Investigación Príncipe FelipeValenciaSpain
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Li Y, Su Y, Zhao Y, Hu X, Zhao G, He J, Wan S, Lü M, Cui H. Demethylzeylasteral inhibits proliferation, migration, and invasion through FBXW7/c-Myc axis in gastric cancer. MedComm (Beijing) 2021; 2:467-480. [PMID: 34766156 PMCID: PMC8554662 DOI: 10.1002/mco2.73] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the most familiar malignancy in the digestive system. Demethylzeylasteral (Dem), a natural functional monomer extracted from Tripterygium wilfordii Hook F, shows anti‐tumor effects in a variety of cancers, including GC, however, with the underlying mechanism poorly understood. In our study, we show that Dem inhibits the proliferation, migration, and invasion of GC cells, which are mediated by down‐regulating c‐Myc protein levels. Mechanistically, Dem reduces the stability of c‐Myc by up‐regulating FBXW7, an E3 ubiquitin ligase. Moreover, in xenograft tumor model experiment, Dem also inhibits GC, which depends on suppressing c‐Myc expression. Finally, Dem enhances GC cell chemosensitivity to the combination treatment of 5‐Fluorouracil (5‐Fu) and doxorubicin (DOX) in vitro. Together, Dem exerts anti‐neoplastic activities through destabilizing and suppressing c‐Myc, establishing a theory foundation for using it in future treatment of GC.
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Affiliation(s)
- Yongsen Li
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Yongyue Su
- Department of Orthopaedic 920th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army Kunming China
| | - Yuzu Zhao
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Xiaosong Hu
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Jiang He
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Sicheng Wan
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China
| | - Muhan Lü
- Department of Gastroenterology The Affiliated Hospital of Southwest Medical University Luzhou China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology College of Sericulture Textile and Biomass sciences Southwest University Chongqing China.,Department of Gastroenterology The Affiliated Hospital of Southwest Medical University Luzhou China.,Cancer Centre Medical Research Institute Southwest University Chongqing China
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6
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Li C, Deng C, Pan G, Wang X, Zhang K, Dong Z, Zhao G, Tan M, Hu X, Shi S, Du J, Ji H, Wang X, Yang L, Cui H. Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:230. [PMID: 33126914 PMCID: PMC7602321 DOI: 10.1186/s13046-020-01743-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
Background Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. Methods The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry). Results In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14–1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. Conclusions The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.
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Affiliation(s)
- Chongyang Li
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Chaowei Deng
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Guangzhao Pan
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Xue Wang
- Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400014, China
| | - Kui Zhang
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Mengqin Tan
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Xiaosong Hu
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Shaomin Shi
- The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050021, China.,The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Juan Du
- The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Haoyan Ji
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China. .,Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China. .,Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China. .,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China.
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7
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Gao PF, Huang D, Wen JY, Liu W, Zhang HW. Advances in the role of exosomal non-coding RNA in the development, diagnosis, and treatment of gastric cancer (Review). Mol Clin Oncol 2020; 13:101-108. [PMID: 32714531 DOI: 10.3892/mco.2020.2068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Exosomes are small vesicles secreted by a variety of cells that contain vrious biological macromolecules, including RNA, non-coding RNA and protein. An increasing number of studies have demonstrated that exosomes and particularly the non-coding RNAs they contain, serve important roles in many cellular processes, including the transmission of information. It is well established that the occurrence and development of gastric cancer, one of the four most common malignant tumors worldwide, involves the transmission of information. Based on the urgent need for the elucidation of the mechanism involved in this process, as well as advances in the diagnosis and treatment of gastric cancer, numerous reports have assessed the association between non-coding RNAs in exosomes and gastric cancer. The purpose of the present review was to summarize recent evidence on certain non-coding RNAs associated with the development, diagnosis and treatment of gastric cancer.
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Affiliation(s)
- Peng-Fei Gao
- Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Da Huang
- Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jun-Yan Wen
- Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Wei Liu
- Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hong-Wu Zhang
- Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Wu L, Lin Y, Feng J, Qi Y, Wang X, Lin Q, Shi W, Zheng E, Wang W, Hou Z, Lin H, Yu C, He Y, Xu Y, Yang H, Lin L, Li L. The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Cancer Cell Int 2019; 19:222. [PMID: 31467488 PMCID: PMC6712616 DOI: 10.1186/s12935-019-0936-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 08/18/2019] [Indexed: 11/10/2022] Open
Abstract
Background Myeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation. Methods The immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients. Results By screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer. Conclusions The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers.
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Affiliation(s)
- Lanqin Wu
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Yingying Lin
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Jinan Feng
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Yuanlin Qi
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Xinrui Wang
- 2State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiaofa Lin
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Wanyan Shi
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Enrun Zheng
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Wei Wang
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Zhenzhu Hou
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Hanbin Lin
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Cheng Yu
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Yan He
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Yan Xu
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Hong Yang
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Ling Lin
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China
| | - Lisheng Li
- 1The School of Basic Medical Sciences, Fujian Medical University, Minhou, Fuzhou China.,3Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou China
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9
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Park SH, Lee DH, Kim JL, Kim BR, Na YJ, Jo MJ, Jeong YA, Lee SY, Lee SI, Lee YY, Oh SC. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. Oncotarget 2018; 7:59503-59518. [PMID: 27517746 PMCID: PMC5312327 DOI: 10.18632/oncotarget.11147] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 07/06/2016] [Indexed: 01/09/2023] Open
Abstract
Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.
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Affiliation(s)
- Seong Hye Park
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Dae-Hee Lee
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea.,Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jung Lim Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Bo Ram Kim
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Yoo Jin Na
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Min Jee Jo
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Yoon A Jeong
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Suk-Young Lee
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sun Il Lee
- Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yong Yook Lee
- The Korean Ginseng Research Institute, Daejeon, Republic of Korea
| | - Sang Cheul Oh
- Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea.,Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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10
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Dalvi S, El Jabbour T, Kim S, Sheehan C, Ross J. Myeloid cell leukemia-1 protein expression and myeloid cell leukemia-1 gene amplification in non small cell lung cancer. INDIAN J PATHOL MICR 2018; 61:27-30. [DOI: 10.4103/ijpm.ijpm_731_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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11
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Low plasma levels of miR-101 are associated with tumor progression in gastric cancer. Oncotarget 2017; 8:106538-106550. [PMID: 29290969 PMCID: PMC5739754 DOI: 10.18632/oncotarget.20860] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 08/15/2017] [Indexed: 12/16/2022] Open
Abstract
Background Several studies have identified the decreased expression of the tumor suppressor miR-101 in various cancers. In this study, we tested miR-101 as a potential therapeutic target and novel plasma biomarker for gastric cancer (GC). Results The miR-101 expression level was significantly lower in GC tissues (P = 0.0038) and GC cell lines (P = 0.0238) than in normal gastric mucosa. Both exosomal and plasma miR-101 were significantly downregulated in GC patients compared with healthy volunteers (P = 0.0281 and P < 0.0001, respectively). Low miR-101 plasma level was significantly associated with advanced T factor, advanced disease stage, and peritoneal metastasis and predicted poor prognosis in GC patients (P = 0.0368; hazard ratio, 3.079; 95% confidence interval: 1.06–11.08). Overexpression of miR-101 in GC cells induced apoptosis by inhibiting MCL1 and suppressed cell migration and invasion by regulating ZEB1. Conclusions Depletion of the tumor suppressor miRNA-101 in plasma is related to tumor progression and poor outcomes. Low plasma miR-101 may be a biomarker for GC, and its restoration might be a novel anticancer treatment strategy.
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12
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Cao S, Yu Y, Chen S, Lei D, Wang S, Pan X, Peng J. Inhibition of CDK9 induces apoptosis and potentiates the effect of cisplatin in hypopharyngeal carcinoma cells. Biochem Biophys Res Commun 2016; 482:536-541. [PMID: 27847320 DOI: 10.1016/j.bbrc.2016.11.049] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 11/10/2016] [Indexed: 12/14/2022]
Abstract
Myeloid cell leukemia-1 (Mcl-1) plays an important role in survival, chemo- and radioresistance of head and neck squamous cell carcinoma (HNSCC). Cyclin-dependent kinase 9/cyclin T (CDK9) promotes excessive production of multiple pro-survival proteins including Mcl-1, leading to impaired apoptosis of cancer cells. As such, CDK9 is an emerging therapeutic target in cancer therapy. We herein report the first study of targeting CDK9 as a treatment strategy for hypopharyngeal squamous cell carcinoma (HSCC), an aggressive malignancy associated with one of the worst prognoses within HNSCC. We showed that mRNA levels of Mcl-1 were significantly higher in HSCC tumor tissues than in the adjacent non-tumor mucosae. In addition, the levels of Mcl-1 mRNA correlated with the tumor size and clinical stage of HSCC patients. CDKI-73, a potent CDK9 inhibitor, was capable of downregulating the expression of Mcl-1 in the HSCC cells by suppression of the CDK9 mediated phosphorylation of RNA polymerase II. CDKI-73 effectively induced apoptosis as a single agent and synergized anti-tumor activity of cisplatin in HSCC cells. Taken together, our study presents compelling evidence for developing CDK9 inhibitors, such as CDKI-73, as new therapeutic strategy for HSCC.
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Affiliation(s)
- Shengda Cao
- Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China
| | - Yingyi Yu
- Department of Hematology, Qilu Hospital, Shandong University, Shandong, PR China
| | - Shangren Chen
- Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China
| | - Dapeng Lei
- Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China
| | - Shudong Wang
- Centre for Drug Discovery and Development, Sansom Institute of Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA5000, Australia
| | - Xinliang Pan
- Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China.
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Shandong University, Shandong, PR China.
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13
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Yin J, Li Y, Zhao H, Qin Q, Li X, Huang J, Shi Y, Gong S, Liu L, Fu X, Nie S, Wei S. Copy-number variation of MCL1 predicts overall survival of non-small-cell lung cancer in a Southern Chinese population. Cancer Med 2016; 5:2171-9. [PMID: 27264345 PMCID: PMC4898974 DOI: 10.1002/cam4.774] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 04/24/2016] [Accepted: 04/26/2016] [Indexed: 12/18/2022] Open
Abstract
BCL2L1 and MCL1 are key anti‐apoptotic genes, and critical for cancer progression. The prognostic values of BCL2L1 and MCL1 copy‐number variations (CNVs) in non‐small‐cell lung cancer (NSCLC) remain largely unknown. Somatic CNVs in BCL2L1 and MCL1 genes were tested in tumor tissues from 516 NSCLC patients in southern China; afterward, survival analyses were conducted with overall survival (OS) as outcome. Additionally, the associations between CNVs and mRNA expression levels were explored using data from 986 NSCLC patients in the Cancer Genome Atlas project. It was found that amplifications of BCL2L1 and MCL1 were associated with unfavorable OS of NSCLC, with adjusted hazards ratio of 1.62 (95% confident interval [CI] = 1.10–2.40; P = 0.015) and 1.39 (95% CI = 1.05–1.84; P = 0.020), respectively. Amplifications of MCL1, but not BCL2L1, were related with higher mRNA expression levels of corresponding gene, compared with non‐amplifications (P = 0.005). Interestingly, after incorporating with MCL1 CNV status, clinical variables (age, sex, TNM stage, and surgical approach) showed an improved discriminatory ability to classify OS (area under curve increased from 72.2% to 74.1%; P = 0.042, DeLong's test). Overall, MCL1 CNV might be a prognostic biomarker for NSCLC, and additional investigations are needed to validate our findings.
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Affiliation(s)
- Jieyun Yin
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Epidemiology and Biostatistics, School of Public Health, Medical College of Soochow University, 199 Ren-ai Road Industrial Park District, Suzhou, China
| | - Yangkai Li
- Department of Thoracic Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Zhao
- Department of Social Science and Public Health, School of Basic Medical Science, Jiujiang University, No. 17, Lufeng Road, Jiujiang, 332000, China
| | - Qin Qin
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaorong Li
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiao Huang
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Shi
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shufang Gong
- Department of Thoracic Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Li Liu
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangning Fu
- Department of Thoracic Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shaofa Nie
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Wei
- Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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14
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Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, Siegelin MD, Fimognari C, Kumar NB, Dou QP, Yang H, Samadi AK, Russo GL, Spagnuolo C, Ray SK, Chakrabarti M, Morre JD, Coley HM, Honoki K, Fujii H, Georgakilas AG, Amedei A, Niccolai E, Amin A, Ashraf SS, Helferich WG, Yang X, Boosani CS, Guha G, Bhakta D, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Keith WN, Bilsland A, Halicka D, Nowsheen S, Azmi AS. Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 2015; 35 Suppl:S78-S103. [PMID: 25936818 PMCID: PMC4720504 DOI: 10.1016/j.semcancer.2015.03.001] [Citation(s) in RCA: 596] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 03/04/2015] [Accepted: 03/04/2015] [Indexed: 12/15/2022]
Abstract
Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.
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Affiliation(s)
- Ramzi M Mohammad
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States; Interim translational Research Institute, Hamad Medical Corporation, Doha, Qatar.
| | - Irfana Muqbil
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
| | - Leroy Lowe
- Getting to Know Cancer, Truro, Nova Scotia, Canada
| | - Clement Yedjou
- C-SET, [Jackson, #229] State University, Jackson, MS, United States
| | - Hsue-Yin Hsu
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
| | - Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Markus David Siegelin
- Department of Pathology and Cell Biology, Columbia University, New York City, NY, United States
| | - Carmela Fimognari
- Dipartimento di Scienze per la Qualità della Vita Alma Mater Studiorum-Università di Bologna, Italy
| | - Nagi B Kumar
- Moffit Cancer Center, University of South Florida College of Medicine, Tampa, FL, United States
| | - Q Ping Dou
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States; Departments of Pharmacology and Pathology, Karmanos Cancer Institute, Detroit MI, United States
| | - Huanjie Yang
- The School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | | | - Gian Luigi Russo
- Institute of Food Sciences National Research Council, Avellino, Italy
| | - Carmela Spagnuolo
- Institute of Food Sciences National Research Council, Avellino, Italy
| | - Swapan K Ray
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Mrinmay Chakrabarti
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - James D Morre
- Mor-NuCo, Inc, Purdue Research Park, West Lafayette, IN, United States
| | - Helen M Coley
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - Alexandros G Georgakilas
- Department of Physics, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, university of florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, university of florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, United Arab Emirates; Faculty of Science, Cairo University, Egypt
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, United Arab Emirates
| | - William G Helferich
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Xujuan Yang
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Chandra S Boosani
- Department of BioMedical Sciences, School of Medicine Creighton University, Omaha NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | | | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Italy
| | - Sophie Chen
- Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue, West Lafayette, IN, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Ireland
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Ireland
| | - Dorota Halicka
- Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
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15
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Lee WS, Kim N, Park YR, Oh HH, Myung E, Kim SH, Yu HM, Kim MY, Oak CY, Chung CY, Park HC, Myung DS, Cho SB, Joo YE. Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells. Oncol Rep 2015; 34:1011-6. [PMID: 26058661 DOI: 10.3892/or.2015.4040] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 05/04/2015] [Indexed: 11/06/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a critical process that occurs during cancer progression, and cancer stem cells have been shown to acquire the EMT phenotype. Myeloid cell leukemia-1 (Mcl-1) has been implicated in cancer progression and is overexpressed in a variety of human cancers. However, the interaction between Mcl-1 and EMT in human gastric cancer (GC) is unclear. We investigated the impact of Mcl-1 expression levels on EMT and the underlying signaling pathways in human GC cells. We used the human GC cell lines, AGS and SNU638, and small interfering RNAs (siRNAs) to evaluate the effects of Mcl-1 knockdown on cell adhesion, migration and invasion. Expression of Mcl-1 and other target genes was determined using reverse transcription-polymerase chain reaction assays and western blotting. The results revealed that expression levels of Mcl-1 mRNA and protein in the AGS and SNU638 cells were reduced following transfection with Mcl-1 siRNAs. Knockdown of Mcl-1 led to increased cellular adhesion to fibronectin and collagen. Expression levels of vimentin, MMP-2, MMP-9 and Snail protein were decreased following knockdown of Mcl-1. However, expression of E-cadherin was increased in the AGS cells following knockdown of Mcl-1. The expression of cancer stemness markers, such as CD44 and CD133, was not altered by knockdown of Mcl-1. Knockdown of Mcl-1 suppressed tumor cell migration and invasion in both human GC cell lines. Signaling cascades, including the β-catenin, MEK1/2, ERK1/2 and p38 pathways, were significantly blocked by knockdown of Mcl-1. Our results indicate that Mcl-1 expression induces EMT via β-catenin, MEK1/2 and MAPK signaling pathways, which subsequently stimulates the invasive and migratory capacity of human GC cells.
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Affiliation(s)
- Wan-Sik Lee
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Nuri Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Young-Ran Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Hyung-Hoon Oh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Eun Myung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Seung-Hun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Hyung-Min Yu
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Mi-Young Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Chan-Young Oak
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Cho-Yun Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Hyung-Chul Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Dae-Seong Myung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Sung-Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
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16
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Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KLB, Ding H, Nowakowski GS, Dai H, Kaufmann SH. Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:1658-71. [PMID: 25827952 DOI: 10.1016/j.bbamcr.2015.03.012] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/20/2015] [Accepted: 03/22/2015] [Indexed: 02/07/2023]
Abstract
Bcl-2, the founding member of a family of apoptotic regulators, was initially identified as the protein product of a gene that is translocated and overexpressed in greater than 85% of follicular lymphomas (FLs). Thirty years later we now understand that anti-apoptotic Bcl-2 family members modulate the intrinsic apoptotic pathway by binding and neutralizing the mitochondrial permeabilizers Bax and Bak as well as a variety of pro-apoptotic proteins, including the cellular stress sensors Bim, Bid, Puma, Bad, Bmf and Noxa. Despite extensive investigation of all of these proteins, important questions remain. For example, how Bax and Bak breach the outer mitochondrial membrane remains poorly understood. Likewise, how the functions of anti-apoptotic Bcl-2 family members such as eponymous Bcl-2 are affected by phosphorylation or cancer-associated mutations has been incompletely defined. Finally, whether Bcl-2 family members can be successfully targeted for therapeutic advantage is only now being investigated in the clinic. Here we review recent advances in understanding Bcl-2 family biology and biochemistry that begin to address these questions.
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Affiliation(s)
- Cristina Correia
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Sun-Hee Lee
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - X Wei Meng
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Nicole D Vincelette
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Katherine L B Knorr
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Husheng Ding
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Grzegorz S Nowakowski
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Haiming Dai
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
| | - Scott H Kaufmann
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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17
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Lee WS, Park YL, Kim N, Oh HH, Son DJ, Kim MY, Oak CY, Chung CY, Park HC, Kim JS, Myung DS, Cho SB, Joo YE. Myeloid cell leukemia-1 regulates the cell growth and predicts prognosis in gastric cancer. Int J Oncol 2015; 46:2154-62. [PMID: 25672320 DOI: 10.3892/ijo.2015.2890] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 01/29/2015] [Indexed: 11/06/2022] Open
Abstract
The expression of myeloid cell leukemia-1 (Mcl‑1), a member of the anti-apoptotic Bcl-2 protein family, has been associated with tumor progression and adverse patient outcome. The aims of current study were to evaluate whether Mcl-1 affects the survival or death of gastric cancer cells, and to investigate the prognostic value of its expression in gastric cancer. PcDNA3.1-Mcl-1 expression and Mcl-1 siRNA vectors were used to overexpress and silence Mcl-1 expression in gastric cancer cell lines including SNU638 and TMK1, respectively. Immunohistochemistry was used to determine the expression of Mcl-1 in gastric cancer tissues. Apoptosis was determined by the TUNEL assay, and cell proliferation was determined by immunostaining with a Ki-67 antibody. Mcl-1 knockdown induced apoptosis through the upregulation of caspase-3, and -7, and PARP activity, and the release of Smac/DIABLO and Omi/HtrA2 into the cytoplasm. Additionally, cell cycle arrest occurred due to decrease of cyclin D1, cell division cycle gene 2 (cdc2), and cyclin-dependent kinase 4 and 6. In contrast, overexpression of Mcl-1 inhibited apoptosis and cell cycle arrest. Mcl-1 knockdown did not suppress tumor cell proliferation in gastric cancer cells, whereas overexpression of Mcl-1 enhanced tumor cell proliferation. The JAK2 and STAT3 signaling cascades were significantly blocked by Mcl-1 knockdown. The mean Ki-67 labeling index (KI) value of Mcl-1 positive tumors was significantly lower than that of Mcl-1 negative tumors. However, there was no significant difference between Mcl-1 expression and the apoptotic index (AI). Mcl-1 expression was significantly increased in gastric cancer tissues compared to normal gastric mucosa tissues, and was associated with age, tumor size, stage, depth of invasion, lymph node metastasis and poor survival. Our study showed that Mcl-1 regulates the cell growth and might be a potential prognostic marker for gastric cancer.
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Affiliation(s)
- Wan-Sik Lee
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Lan Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Nuri Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Hyung-Hoon Oh
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Dong-Jun Son
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Mi-Young Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Chan-Young Oak
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Cho-Yun Chung
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Hyung-Chul Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Jong-Sun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Dae-Seong Myung
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Sung-Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
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18
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Modugno M, Banfi P, Gasparri F, Borzilleri R, Carter P, Cornelius L, Gottardis M, Lee V, Mapelli C, Naglich JG, Tebben A, Vite G, Pastori W, Albanese C, Corti E, Ballinari D, Galvani A. Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers. Exp Cell Res 2014; 332:267-77. [PMID: 25486070 DOI: 10.1016/j.yexcr.2014.11.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 11/27/2014] [Accepted: 11/28/2014] [Indexed: 01/16/2023]
Abstract
Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.
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Affiliation(s)
- Michele Modugno
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
| | - Patrizia Banfi
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Fabio Gasparri
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Robert Borzilleri
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Percy Carter
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Lyndon Cornelius
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Marco Gottardis
- Janssen, Pharmaceutical Companies of Johnson and Johnson, 1400 McKean Rd, Spring House, Ambler, PA 19002, USA
| | - Ving Lee
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Claudio Mapelli
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Joseph G Naglich
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Andrew Tebben
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Gregory Vite
- Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA
| | - Wilma Pastori
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Clara Albanese
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Emiliana Corti
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Dario Ballinari
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
| | - Arturo Galvani
- Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy
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Hu CJ, Wang B, Tang B, Chen BJ, Xiao YF, Qin Y, Yong X, Luo G, Zhang JW, Zhang D, Li S, He F, Yang SM. The FOXM1-induced resistance to oxaliplatin is partially mediated by its novel target gene Mcl-1 in gastric cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:290-9. [PMID: 25482013 DOI: 10.1016/j.bbagrm.2014.11.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 11/24/2014] [Accepted: 11/26/2014] [Indexed: 02/07/2023]
Abstract
Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that belongs to the Bcl-2 family. The aberrant expression of Mcl-1 is important for sensitivity to chemotherapy drugs in gastric cancer. However, the regulatory mechanism of Mcl-1 in gastric cancer cells remains unclear. In this study, we first found that Forkhead box M1 (FOXM1) and Mcl-1 expression levels were positively correlated in human gastric cancer specimens and that both are associated with poor prognosis of patients treated with oxaliplatin. Second, we demonstrated that the expression level of Mcl-1 was correlated with FOXM1 expression in gastric cancer cells. Third, reporter assays showed that FOXM1 upregulated the promoter activity of the Mcl-1 gene. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrated that FOXM1 could bind to a particular site (-635acaaacaa-628) in the promoter region of the Mcl-1 gene. Moreover, CCK-8 assays and analyses of apoptosis revealed that the suppression of the FOXM1/Mcl-1 pathway induced apoptosis and thus increased sensitivity to oxaliplatin in gastric cancer cells, whereas the enhancement of the FOXM1/Mcl-1 pathway inhibited apoptosis and decreased sensitivity to oxaliplatin in gastric cancer cells. Taken together, this study is the first to not only show that Mcl-1 is a novel target gene of FOXM1 but also suggest that targeting FOXM1/Mcl-1 may be a novel strategy to enhance sensitivity to oxaliplatin in gastric cancer.
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Affiliation(s)
- Chang-Jiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Bin Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Bai-jun Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yu-Feng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yong Qin
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Xin Yong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Gang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Jian-Wei Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Dan Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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Palve V, Mallick S, Ghaisas G, Kannan S, Teni T. Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers. PLoS One 2014; 9:e111927. [PMID: 25409302 PMCID: PMC4237324 DOI: 10.1371/journal.pone.0111927] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 10/09/2014] [Indexed: 12/28/2022] Open
Abstract
Background Altered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells. Methods The expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed. Results Anti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (P<0.02). In oral cancer patients, high Mcl-1L expression was significantly associated with node positivity (P = 0.021), advanced tumor size (P = 0.013) and poor overall survival (P = 0.002). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for oral cancers (P = 0.037). Mcl-1L shRNA knockdown or its inhibition by Obatoclax in combination with Cisplatin synergistically reduced viability and growth of oral cancer cells than either treatment alone. Conclusion Our studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.
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Affiliation(s)
- Vinayak Palve
- Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India
| | - Sanchita Mallick
- Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India
| | - Gauri Ghaisas
- Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India
| | - Sadhana Kannan
- Epidemiology and Clinical Trial Unit (ECTU), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India
| | - Tanuja Teni
- Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India
- * E-mail:
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Rath S, Das L, Kokate SB, Pratheek BM, Chattopadhyay S, Goswami C, Chattopadhyay R, Crowe SE, Bhattacharyya A. Regulation of Noxa-mediated apoptosis in Helicobacter pylori-infected gastric epithelial cells. FASEB J 2014; 29:796-806. [PMID: 25404713 DOI: 10.1096/fj.14-257501] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Helicobacter pylori induces the antiapoptotic protein myeloid cell leukemia 1 (Mcl1) in human gastric epithelial cells (GECs). Apoptosis of oncogenic protein Mcl1-expressing cells is mainly regulated by Noxa-mediated degradation of Mcl1. We wanted to elucidate the status of Noxa in H. pylori-infected GECs. For this, various GECs such as AGS, MKN45, and KATO III were either infected with H. pylori or left uninfected. The effect of infection was examined by immunoblotting, immunoprecipitation, chromatin immunoprecipitation assay, in vitro binding assay, flow cytometry, and confocal microscopy. Infected GECs, surgical samples collected from patients with gastric adenocarcinoma as well as biopsy samples from patients infected with H. pylori showed significant up-regulation of both Mcl1 and Noxa compared with noninfected samples. Coexistence of Mcl1 and Noxa was indicative of an impaired Mcl-Noxa interaction. We proved that Noxa was phosphorylated at Ser(13) residue by JNK in infected GECs, which caused cytoplasmic retention of Noxa. JNK inhibition enhanced Mcl1-Noxa interaction in the mitochondrial fraction of infected cells, whereas overexpression of nonphosphorylatable Noxa resulted in enhanced mitochondria-mediated apoptosis in the infected epithelium. Because phosphorylation-dephosphorylation can regulate the apoptotic function of Noxa, this could be a potential target molecule for future treatment approaches for H. pylori-induced gastric cancer.
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Affiliation(s)
- Suvasmita Rath
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Lopamudra Das
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Shrikant Babanrao Kokate
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - B M Pratheek
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Subhasis Chattopadhyay
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Chandan Goswami
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Ranajoy Chattopadhyay
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Sheila Eileen Crowe
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Asima Bhattacharyya
- *National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; and Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
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22
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Hsu KH, Tsai HW, Lin PW, Hsu YS, Lu PJ, Shan YS. Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors. World J Surg Oncol 2014; 12:189. [PMID: 24947165 PMCID: PMC4080696 DOI: 10.1186/1477-7819-12-189] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/12/2014] [Indexed: 01/04/2023] Open
Abstract
Background Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs. Methods The expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance. Results Up-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically. Conclusions Our study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.
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Affiliation(s)
| | | | | | | | | | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan.
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Yu L, Liu S. Autophagy contributes to modulating the cytotoxicities of Bcl-2 homology domain-3 mimetics. Semin Cancer Biol 2013; 23:553-60. [PMID: 24012660 DOI: 10.1016/j.semcancer.2013.08.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/27/2013] [Indexed: 01/08/2023]
Abstract
The dysregulation of apoptosis is a key step in developing cancers, and mediates resistance to cancer therapy. Commitment to apoptosis is caused by permeabilization of the outer mitochondrial membrane, a process regulated by the interactions between different proteins of Bcl-2 family. Furthermore, Bcl-2 family proteins also bind to the endoplasmic reticulum, where they modulate autophagy, another important pathway regulating cell survival and death. Dysregulation of Bcl-2 family has been demonstrated in a wide spectrum of human cancers, including gastrointestinal cancers. Therefore, targeting the Bcl-2 family of proteins represents a promising therapeutic approach for these malignancies. Recent advances have yielded small molecules that have close structural or functional similarity to BH3-only proteins and are therefore named BH3 mimetics. Of these BH3 mimetics, obatoclax, (-)-gossypol, and ABT-263 are currently in clinical trials for multiple cancers. Growing evidence indicates that these BH3 mimetics not only induce apoptosis, but also regulate autophagy which may serve as a pro-survival or pro-death mechanism to counteract or mediate the cytotoxicity of BH3 mimetics. This review discusses the role of autophagy in cell-fate decision upon BH3 mimetics treatment. Further exploration of our understanding of the association between autophagy and cellular outcomes in response to BH3 mimetics treatment will likely offer improved therapies for patients with cancer.
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Affiliation(s)
- Le Yu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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Tan K, Goldstein D, Crowe P, Yang JL. Uncovering a key to the process of metastasis in human cancers: a review of critical regulators of anoikis. J Cancer Res Clin Oncol 2013; 139:1795-805. [PMID: 23912151 DOI: 10.1007/s00432-013-1482-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 07/19/2013] [Indexed: 12/28/2022]
Abstract
PURPOSE Anoikis ('homelessness' in Greek) is a form of apoptosis following the detachment of cells from the appropriate extracellular matrix (Chiarugi and Giannoni in Biochem Pharmacol 76:1352-1364, 2008). Resistance to anoikis is a critical mediator of metastasis in cancer by enabling cancer cells to survive during invasion and transport in the blood and lymph. Numerous regulators and mechanisms of anoikis in human cancer have been proposed to date. Consequently, the identification of key regulators of anoikis that can be targeted to at least partially restore anoikis sensitivity in cancer cells is important in the development of therapies to treat metastatic cancer. METHODS A literature search focusing on the regulators of anoikis in human cancer was performed on the Medline, Embase and Scopus databases. RESULTS Mcl-1, Cav-1, Bcl-(xL), cFLIP, 14-3-3ζ and Bit1 appear to regulate anoikis in human cancer by participating in the intrinsic apoptotic pathway, extrinsic apoptotic pathway or caspase-independent pathways. Mcl-1, Cav-1, Bcl-(xL), cFLIP and 14-3-3ζ are suppressors of anoikis, and their upregulation confers anoikis resistance to cancer cells. Bit1 is a promoter of anoikis and is downregulated to confer anoikis resistance in metastatic cancer. CONCLUSION Anoikis is a complex process involving the crosstalk between different signalling pathways. The dysregulated expression of key regulators of anoikis that participate in these signalling pathways promotes anoikis resistance in human cancer. These regulators of anoikis might therefore be the targets for developing therapies to overcome anoikis resistance in metastatic cancer.
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Affiliation(s)
- Kevin Tan
- Adult Cancer Program, Sarcoma and Nano-Oncology Research Group, Faculty of Medicine, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Room 209, Sydney, NSW, 2052, Australia
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Micheau O, Shirley S, Dufour F. Death receptors as targets in cancer. Br J Pharmacol 2013; 169:1723-44. [PMID: 23638798 PMCID: PMC3753832 DOI: 10.1111/bph.12238] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 04/25/2013] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. LINKED ARTICLES This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.
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Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. Gastric Cancer 2013; 16:100-10. [PMID: 22527182 DOI: 10.1007/s10120-012-0153-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 03/08/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. METHODS Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. RESULTS Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. CONCLUSION These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.
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Koehler BC, Urbanik T, Vick B, Boger RJ, Heeger S, Galle PR, Schuchmann M, Schulze-Bergkamen H. TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies. World J Gastroenterol 2009; 15:5924-35. [PMID: 20014456 PMCID: PMC2795179 DOI: 10.3748/wjg.15.5924] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors, in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL), on overcoming TRAIL resistance in hepatocellular carcinoma (HCC) and to study the efficacy of agonistic TRAIL antibodies, as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis.
METHODS: Surface expression of TRAIL receptors (TRAIL-R1-4) and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting, respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs. HCC cells were treated with kinase inhibitors and chemotherapeutic drugs. Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
RESULTS: TRAIL-R1 and -R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However, treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates. Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002 [inhibition of phosphoinositol-3-kinase (PI3K)], AG1478 (epidermal growth factor receptor kinase), PD98059 (MEK1), rapamycin (mammalian target of rapamycin) and the multi-kinase inhibitor Sorafenib. Furthermore, the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance: knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells. Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.
CONCLUSION: Our data identify the blockage of survival kinases, combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
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MCL-1V, a novel mouse antiapoptotic MCL-1 variant, generated by RNA splicing at a non-canonical splicing pair. Biochem Biophys Res Commun 2009; 391:492-7. [PMID: 19919825 DOI: 10.1016/j.bbrc.2009.11.086] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 11/12/2009] [Indexed: 11/21/2022]
Abstract
Myeloid cell leukemia-1 (MCL-1) that belongs to BCL-2 family is essential for survival of hematopoietic stem cells. It is upregulated in various types of cancer and promotes cancer cell metastasis. It is known that human MCL-1 gene undergoes differential splicing and yields three mRNAs encoding antiapoptotic MCL-1L and proapoptotic MCL-1S and MCL-1ES. However, no MCL-1 variants have been reported in mouse cells. We report here a new splicing variant of mouse Mcl-1, Mcl-1V, that is expressed in a variety of mouse normal and tumor cell lines and tissues. Comparative sequence analysis of the full-length Mcl-1 and Mcl-1V cDNAs suggested that Mcl-1V mRNA results from splicing within the first coding exon of Mcl-1 gene at a non-canonical donor-acceptor pair. MCL-1V lacks 46 amino acid residues within the N-terminal region of MCL-1. It localizes in mitochondria and inhibits anoxia- and anticancer drug-induced apoptosis as potent as MCL-1, and decayed less rapidly than MCL-1 in the cells undergoing apoptosis. Collectively, our results show that mouse cells ubiquitously express antiapoptotic MCL-1V that may play a role in mitochondrial cell death.
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