Abstract LB-427: Differential effects of resveratrol-induced SIRT1 in prostate cancer: A novel therapeutic target

Abstract

Silence information regulator (SIRT1) is a Nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylase that regulates various biological processes including cell survival, apoptosis, metabolism and aging. Given the role for calorie restriction (CR) in delaying the onset of aging and age-related disorders including cancers, efforts are under way to develop CR mimetics as therapeutic agents. Resveratrol, a CR mimetic activates SIRT1 and has been shown to extend life span. Further, resveratrol has been shown to prevent tumor development and cancer cell proliferation in a wide variety of models including prostate. However the precise role of SIRT1 in prostate cancer development and progression remains unexplored. Towards developing SIRT1 targeted preventive approaches, we conducted studies using human prostate cancer cell lines and a preclinical animal model that develops high grade prostatic intraepithelial neoplasia (HGPIN) in response to hormone stimulation. Our studies show that androgen independent prostate cancer cell lines (DU145 and PC-3) express higher levels of SIRT1 compared to non tumorigenic RWPE-1 consistent with the published results. Resveratrol-mediated inhibition of cell proliferation was associated with reduction in the levels of pAkt (Ser⁴⁷³ and Thr³⁰⁸), SIRT1and Cyclin D1 in PC-3 cells but not in DU145. Most interestingly we did not detect SIRT1 enzymatic activation following resveratrol treatment. Further pretreatment of prostate cancer cells with known pharmacological SIRT1 inhibitor (Nicotinamide) enhanced resveratrol mediated proliferation inhibition. Dietary intervention with increasing doses of resveratrol for 3 weeks showed no protective effect on the development of PIN lesions or chronic inflammation or atrophy in rats stimulated with hormones. Our studies show for the first time that (i) SIRT1 may not be a direct target of resveratrol; (ii) combination of resveratrol and SIRT1inhibitor may provide a new approach to prevent development and progression of prostate cancer. Supported by CA 137518 (APK).

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-427.