title: Resveratrol inhibits protein translation in hepatic cells.
abstract: Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2α. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling.
authors.affiliation: Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island, United States of America. Eugenia_Villa-Cuesta@brown.edu
authors.forename: Eugenia
authors.initials: E
authors.lastname: Villa-Cuesta
authors.forename: Joan M
authors.initials: JM
authors.lastname: Boylan
authors.forename: Marc
authors.initials: M
authors.lastname: Tatar
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gruppuso
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D039562:Eukaryotic Initiation Factor-4F; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol; D020123:Sirolimus