Autophagic cell death induced by resveratrol depends on the Ca(2+)/AMPK/mTOR pathway in A549 cells.

Resveratrol has many biological effects, including anti-tumor, antiviral activities, and vascular protection. Recent studies have suggested that resveratrol exert its antitumor effects through induction of autophagy by an unknown mechanism. In this study, we investigated the involvement of autophagy in resveratrol-induced cell death and its potential molecular mechanisms in A549 human lung adnocarcinoma cells. Resveratrol-induced growth inhibition and cell death was assessed by MTT and clonogenic assays. Activation of autophagy was characterized by monodansylcadaverine, transmission electron microscopy, and expression of autophagy marker protein LC3. Western blot analysis was used to study the cell signals involved in the mechanisms of autophagic death. Intracellular free calcium was detected with Fura2-AM staining. Our results indicated that resveratrol induced A549 cell death was mediated by autophagy. 3-methyladenine, an inhibitor of autophagy, suppressed resveratrol-induced autophagic cell death, and knockdown of autophagy-related genes Atg5 and Beclin-1 with siRNAs reversed RSV-induced cell death. Intracellular free calcium accumulated immediately following resveratrol addition, which led to the activation of phospho-AMPK and phospho-Raptor, and a reduction in the amount of phospho-p70S6K. These effects could be reversed by the AMPK inhibitor compound C, and the calcium ion-chelating agent EGTA. In conclusion, we demonstrate that resveratrol-induced A549 cell death was mediated by the process of autophagic cell death via Ca(2+)/AMPK-mTOR signaling pathway.

Resveratrol-induced apoptosis is enhanced by inhibition of autophagy in esophageal squamous cell carcinoma.

The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.