title: 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.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Heeyoon
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Mi Nam
authors.initials: MN
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Koh
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Ohman
authors.initials: O
authors.lastname: Kwon
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea.
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Noh
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea.
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047908:Intracellular Signaling Peptides and Proteins; D013267:Stilbenes; D000255:Adenosine Triphosphate; D008156:Luciferases; C546842:MTOR protein, human; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D000077185:Resveratrol