Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Dohyun Park; Heeyoon Jeong; Mi Nam Lee; Ara Koh; Ohman Kwon; Yong Ryoul Yang; Jungeun Noh; Pann-Ghill Suh; Hwangseo Park; Sung Ho Ryu

doi:10.1038/srep21772

Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

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

Authors

Dohyun Park¹, Heeyoon Jeong¹, Mi Nam Lee¹, Ara Koh¹, Ohman Kwon², Yong Ryoul Yang³, Jungeun Noh¹, Pann-Ghill Suh³, Hwangseo Park⁴, Sung Ho Ryu^{1

2}

Affiliations

¹ Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
² School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
³ School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea.
⁴ Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea.

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
Autophagy-Related Protein-1 Homolog
TOR Serine-Threonine Kinases
ULK1 protein, human
Resveratrol