ArticleOncotarget2016
Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- Prognostic role of metformin intake in diabetic patients with colorectal cancer: An updated qualitative evidence of cohort studies.Oncotarget · 2017 · on this mapPooled it
- Targeted Degradation of MCL-1 by PROTAC Mcl-1 Degrader-1 Exhibits Antiproliferative and Antimigratory Effects and Triggers Mitochondria-Mediated Apoptosis in Colorectal Cancer.Current issues in molecular biology · 2026Article
- Metformin in gastrointestinal cancers and inflammatory bowel disease: Unraveling its mechanisms and therapeutic applications.iScience · 2026Review
- Metformin: A Dual-Role Player in Cancer Treatment and Prevention.International journal of molecular sciences · 2024Review
- Mcl-1 Protein and Viral Infections: A Narrative Review.International journal of molecular sciences · 2024Review
- The involvement of E3 ubiquitin ligases in the development and progression of colorectal cancer.Cell death discovery · 2023Review
- The Role of HECT E3 Ubiquitin Ligases in Colorectal Cancer.Biomedicines · 2023Review
- Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC.Molecular therapy oncolytics · 2021Article
- The Anti-Tumor Effect ofCancers · 2021Article
- Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects.Journal of experimental & clinical cancer research : CR · 2019Review
- Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells.Cancers · 2019Review
- Article
- Metformin-induced apoptosis facilitates degradation of the cellular caspase 8 (FLICE)-like inhibitory protein through a caspase-dependent pathway in human renal cell carcinoma A498 cells.Oncology letters · 2018Article
- Article
- Review
- Overexpression of miR-101 promotes TRAIL-induced mitochondrial apoptosis in papillary thyroid carcinoma by targeting c-met and MCL-1.Oncotarget · 2017Article
- Therapeutic strategies against cancer stem cells in human colorectal cancer.Oncology letters · 2017Article
- Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway.Oncotarget · 2017Article
- Knockdown of miR-27a sensitizes colorectal cancer stem cells to TRAIL by promoting the formation of Apaf-1-caspase-9 complex.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.