Abstract 2585: Resveratrol induces autophagy in prostate cancer cells and intervention suppresses the progression of PIN in animals

Abstract

Abstract Resveratrol (3,4′-trihydroxystilbene), a natural product is present in significant concentrations in red wine, peanuts, walnuts etc. Emerging evidence indicates that resveratrol exerts antitumorigenic activity in various tumor models including prostate. Although multiple biological effects on proliferation, apoptosis and activation of SIRT1 have been demonstrated to be associated with resveratrol-induced activities, the precise mechanism associated with resveratrol-induced SIRT1 activation and cancer cell growth inhibition remains unclear. In addition, whether resveratrol intervention suppresses the development and progression of PIN (Prostatic Intraepithelial Neoplasia) is unknown. In this study, we examined the role of SIRT1 and the underlying mechanism involved in resveratrol-mediated biological effects. Our results show that although resveratrol significantly inhibited proliferation of multiple prostate cell lines including RWPE-1, C42B, PC3 and DU145 at higher concentrations (> 50 µM); however, at lower concentrations (< 25 µM), resveratrol prompted cell proliferation. Interestingly androgen responsive LNCaP cells exhibited resistance to resveratrol-mediated inhibition of cell proliferation. Under these experimental conditions, we also observed significant increase in autophagy without remarkable increase in apoptosis. Given the role of Akt/mTOR signaling pathway as a negative regulator of autophagy, we investigated whether resveratrol induce autophagy via modulation of Akt/mTOR signaling. Our data indicate that resveratrol-induced autophagy was associated with decreased levels of mTORC1 activity and increased SIRT1 expression. Knockdown of SIRT1 enhanced prostate cell proliferation and attenuated resveratrol-induced autophagy. Using prostate specific PTEN−/− mice, we found that dietary administration of resveratrol reduced the incidence of high-grade PIN lesions significantly. These findings implicated an important role for mTORC1/SIRT1 signaling axis in mediating resveratrol-induced upregulation of autophagy and inhibition of apoptosis. [Supported by NIH CA137578 (APK)] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2585. doi:1538-7445.AM2012-2585