Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Abstract

Resveratrol (RSV) is a natural polyphenol that has a beneficial effect on health, and resveratrol-induced autophagy has been suggested to be a key process in mediating many beneficial effects of resveratrol, such as reduction of inflammation and induction of cancer cell death. Although various resveratrol targets have been suggested, the molecule that mediates resveratrol-induced autophagy remains unknown. Here, we demonstrate that resveratrol induces autophagy by directly inhibiting the mTOR-ULK1 pathway. We found that inhibition of mTOR activity and presence of ULK1 are required for autophagy induction by resveratrol. In line with this mTOR dependency, we found that resveratrol suppresses the viability of MCF7 cells but not of SW620 cells, which are mTOR inhibitor sensitive and insensitive cancer cells, respectively. We also found that resveratrol-induced cancer cell suppression occurred ULK1 dependently. For the mechanism of action of resveratrol on mTOR inhibition, we demonstrate that resveratrol directly inhibits mTOR. We found that resveratrol inhibits mTOR by docking onto the ATP-binding pocket of mTOR (i.e., it competes with ATP). We propose mTOR as a novel direct target of resveratrol, and inhibition of mTOR is necessary for autophagy induction.

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling

“…We then investigated the molecular mechanism underlying this apoptotic pathway. Previous reports have suggested that resveratrol has the capability to induce autophagy and might also play a role in enhancing apoptosis [54][55][56]. However, our western blot results revealed that treatment with different concentrations of resveratrol increased LC3-II accumulation and decreased p62 expression levels in A549 cells, thus confirming the activation of complete autophagy flux by lysosomal degradation (Fig.…”

Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

“…It has been determined that resveratrol dose-dependently reduced the vascular endothelial growth factor (VEGF), leptin, interleukin (IL)-6, and IL-8 expression in hypoxia-induced human adipocytes and prevented adipokine-induced inflammation and angiogenesis [51]. In addition, resveratrol induced autophagy by directly inhibiting mTOR in HeLa cells [52]. Prostate cancer cells induced autophagy through inhibition of the Akt/mTOR pathway in PC3 and DU145 cells [53].…”

Effect of Nutrition on Statural Growth

“…In this manner, energy and building blocks can be generated from the cell’s own protein and lipid stores. Nutrient-stimulated activation of mTOR leads to the phosphorylation and inactivation of components of the autophagy pathway [149], specifically ULK1 [148]. This process, shown in the GP [144, 145], is associated with nutrition-induced regulation of growth attenuation.…”

“…When AMP kinase or HIF1α activity were blocked, autophagy could not be activated [147]. mTORC1 suppresses catabolism by inhibiting autophagy through suppression of the autophagy complex ULK1-ATG13-FIP200, specifically through inhibitory phosphorylation of ULK1 [148]. Inhibition of mTORC1 is sufficient to induce autophagy.…”