Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Sci Rep. 2016 Feb 23;6:21772. doi: 10.1038/srep21772.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Motifs
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Autophagy / drug effects*
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Binding, Competitive
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Resveratrol
  • Signal Transduction
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Intracellular Signaling Peptides and Proteins
  • Stilbenes
  • Adenosine Triphosphate
  • Luciferases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human
  • Resveratrol