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Here, we examined the impact of resveratrol\u2010mediated pharmacological activation of SIRT1 on the progression of HGPIN lesions (using the <jats:italic>Pten<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse model) and on prostate tumor development (using an orthotopic model of prostate cancer cells stably silenced for <jats:italic>SIRT1<\/jats:italic>). We show that precise SIRT1 modulation could benefit both cancer prevention and treatment. Positive effect of SIRT1 activation can prevent <jats:italic>Pten<\/jats:italic> deletion\u2010driven development of HGPIN lesions in mice if resveratrol is administered early (pre\u2010cancer stage) with little to no benefit after the establishment of HGPIN lesions or tumor cell implantation. Mechanistically, our results show that under androgen deprivation conditions, SIRT1 inhibition induces senescence as evidenced by decreased gene signature associated with negative regulators of senescence and increased senescence\u2010associated \u03b2\u2010galactosidase activity. Furthermore, pharmacological inhibition of SIRT1 potentiated growth inhibitory effects of clinical androgen receptor\u00a0blockade agents and radiation. Taken together, our findings provide an explanation for the discrepancy regarding the role of SIRT1 in prostate tumorigenesis. Our results reveal that the bifurcated roles for SIRT1 may occur in stage and context\u2010dependent fashion by functioning in an antitumor role in prevention of early\u2010stage prostate lesion development while promoting tumor development and disease progression post\u2010lesion development. Clinically, these data highlight the importance of precise SIRT1 modulation to provide benefits for cancer prevention and treatment including sensitization to conventional therapeutic approaches.<\/jats:p>","DOI":"10.1002\/mc.23412","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T20:45:25Z","timestamp":1650660325000},"page":"702-716","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["SIRT1 inhibition\u2010induced senescence as a strategy to prevent prostate cancer progression"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-2344","authenticated-orcid":false,"given":"Shih\u2010Bo","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine The University of Texas Health at San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Rivas","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine The University of Texas Health at San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine The University of Texas Health at San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics UT Health at San Antonio Greehey Children's Cancer Research Institute San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics UT Health at San Antonio Greehey Children's Cancer Research Institute San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keri L.","family":"Schadler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MD Anderson Cancer Center Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Pharmacy University of Houston Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Reddick","sequence":"additional","affiliation":[{"name":"Department of Pathology The University of Texas Health at San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-4861","authenticated-orcid":false,"given":"Rita","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine The University of Texas Health at San Antonio San Antonio Texas 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