title: Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis.
abstract: SIRT1 (mammalian ortholog of the yeast silent information regulator 2) is a NAD-dependent histone deacetylase belonging to the multigene family of sirtuins. Anecdotal and epidemiologic observations provide evidence for beneficial effects of the calorie restriction mimetic resveratrol (RES), a SIRT1 activator in preventing cardiovascular diseases and cancer. Although SIRT1 possesses both tumorigenic and antitumorigenic potential, the molecular mechanisms underlying SIRT1-mediated tumor progression or inhibition are poorly understood. In this study, we investigated the role of SIRT1 in multiple human prostate cancer cell lines and prostate-specific PTEN knockout mouse model using resveratrol. Androgen-independent prostate cancer cell lines (C42B, PC3, and DU145) express higher levels of SIRT1 than androgen-responsive (LNCaP) and nontumorigenic prostate cells (RWPE-1). Resveratrol enhanced this expression without any significant effect on SIRT1 enzymatic activity. Inhibition of SIRT1 expression using shRNA enhanced cell proliferation and inhibited autophagy by repressing phosphorylation of S6K and 4E-BP1. These biologic correlates were reversed in the presence of resveratrol. Analysis of prostates from dietary intervention with resveratrol showed a significant reduction in prostate weight and reduction in the incidence of high-grade prostatic intraepithelial neoplastic (HGPIN) lesions by approximately 54% with no significant change in body weight. Consistent with the in vitro findings, resveratrol intervention in the PTEN knockout mouse model was associated with reduction in the prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1. These data suggest that SIRT1/S6K-mediated inhibition of autophagy drives prostate tumorigenesis. Therefore, modulation of SIRT1/S6K signaling represents an effective strategy for prostate cancer prevention.
authors.affiliation: Department of Urology, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Guiming
authors.initials: G
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Rivas
authors.forename: Roble
authors.initials: R
authors.lastname: Bedolla
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thapa
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.forename: Rita
authors.initials: R
authors.lastname: Ghosh
authors.forename: Addanki P
authors.initials: AP
authors.lastname: Kumar
mesh_terms: D000821:Animal Feed; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D004032:Diet; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000188:drug therapy* / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000378:metabolism; D000077185:Resveratrol; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D013267:Stilbenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C022616:thiazolyl blue; D000077185:Resveratrol