Activation of autophagy flux by metformin downregulates cellular FLICE–like inhibitory protein and enhances TRAIL- induced apoptosis
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Uddin MD. Nazim1, Ji-Hong Moon1, Ju-Hee Lee1, You-Jin Lee1, Jae-Won Seol1, Seong-Kug Eo1, John-Hwa Lee1, Sang-Youel Park1
1Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
Sang-Youel Park, e-mail: firstname.lastname@example.org
Keywords: metformin, autophagy flux, TRAIL, cancer
Received: November 11, 2015 Accepted: February 29, 2016 Published: March 14, 2016
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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