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.