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.