Activation of Autophagy Flux by Metformin Downregulates Cellular FLICE-Like Inhibitory Protein and Enhances TRAIL- Induced Apoptosis
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// Uddin MD. Nazim 1 , Ji-Hong Moon 1 , Ju-Hee Lee 1 , You-Jin Lee 1 , Jae-Won Seol 1 , Seong-Kug Eo 1 , John-Hwa Lee 1 , Sang-Youel Park 1 1 Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea Correspondence to: Sang-Youel Park, e-mail: sypark@chonbuk.ac.kr Keywords: metformin, autophagy flux, TRAIL, cancer Received: November 11, 2015 Accepted: February 29, 2016 Published: March 14, 2016 ABSTRACT Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL is regarded as one of the most promising anticancer agents, because it can destruct cancer cells without showing any toxicity to normal cells. Metformin is an anti-diabetic drug with anticancer activity by inhibiting tumor cell proliferation. In this study, we demonstrated that metformin could induce TRAIL-mediated apoptotic cell death in TRAIL-resistant human lung adenocarcinoma A549 cells. Pretreatment of metformindownregulation of c-FLIP and markedly enhanced TRAIL-induced tumor cell death by dose-dependent manner. Treatment with metformin resulted in slight increase in the accumulation of microtubule-associated protein light chain LC3-II and significantly decreased the p62 protein levels by dose-dependent manner indicated that metformin induced autophagy flux activation in the lung cancer cells. Inhibition of autophagy flux using a specific inhibitor and genetically modified ATG5 siRNA blocked the metformin-mediated enhancing effect of TRAIL. These data demonstrated that downregulation of c-FLIP by metformin enhanced TRAIL-induced tumor cell death via activating autophagy flux in TRAIL-resistant lung cancer cells and also suggest that metformin may be a successful combination therapeutic strategy with TRAIL in TRAIL-resistant cancer cells including lung adenocarcinoma cells.
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siRNA targeting Atg5 blocks metformin's activation of autophagy flux and cell death in adenocarcinoma cells in culture, albeit based on high concentrations (1 to 4 mM and 12-hour exposure) of metformin.
“Furthermore, siRNA targeting Atg5 blocks metformin’s activation of autophagy flux and cell death in adenocarcinoma cells in culture, albeit based on the use of high concentrations (1 to 4 mM and a 12-hour exposure) of metformin (234).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [234]
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- Authors
- Nazim, U. M., Moon, J.-H., Lee, J.-H., Lee, Y.-J., Seol, J.-W., Eo, S.-K., Lee, J.-H., & Park, S.-Y.
- Affiliations
- Jeonbuk National University (KR)
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2016-03-14
- Volume
- 7
- Issue
- 17
- Pages
- 23468-23481
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5029640
- OpenAlex
- W2299525559
- Cited by
- 58
- References
- 62
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 10 · 2017: 11 · 2016: 2
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- metformin, autophagic flux, TRAIL, TRAIL resistance, c-FLIP, apoptosis, lung adenocarcinoma, A549 cells, LC3-II, p62, ATG5, combination therapy, anticancer agents
- MeSH terms
- Adenocarcinoma, Autophagy, Humans, Hypoglycemic Agents, Lung Neoplasms, Metformin, Tumor Cells, Cultured, Biomarkers, Tumor, Apoptosis, Cell Proliferation, TNF-Related Apoptosis-Inducing Ligand, CASP8 and FADD-Like Apoptosis Regulating Protein
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