SIRT1 as a Resveratrol target in PTEN knockout Prostate Cancer Model

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DESCRIPTION (provided by applicant): Aging is one of the major risk factors for prostate cancer (PCA) which is the second leading cause of cancer related deaths in men. Epidemiological studies show lower incidence of prostate cancer in Oriental population whose dietary habits include consumption of fruits and vegetables. These data implicate non toxic bioactive food components in prostate cancer prevention. Therefore understanding the molecular causative factors associated with the age-dependent increase in the risk of prostate cancer are critical for developing effective strategies for its management. Silent information regulator 1 (SIRT1) has been shown to increase life span implicating a role for SIRT1 in aging. Resveratrol, a phytoalexin found in the skin of grapes, berries and peanuts has been identified as the most potent SIRT1 activator in a screen for identifying modulators of SIRT1 activity. Resveratrol has been shown to inhibit tumor development in various models including prostate. However it is not known if SIRT1 activation can be exploited as a novel cancer-prevention target. As proof of principle we hypothesize that Resveratrol induced SIRT1 activation prevents prostate carcinogenesis through modulation of Akt-mediated activation of NFkB and FOXO3a signaling. To the best of our knowledge the relevance of SIRT1 as a molecular target for preventing prostate cancer in an in vivo model has not been tested. The major objective of this pilot proposal is to demonstrate the (i) importance of SIRT1 signaling in inhibiting prostate cancer cell growth using a variety of molecular and biochemical studies (ii) ability of dietary administration of Resveratrol to prevent prostate cancer using PTEN knock-out mouse model through SIRT1 signaling pathway. We will validate the molecular targets associated with its biological activity using immunohistochemistry, western blotting, RT-PCR and enzymatic activities (SIRT1) from tissue samples. The animal model we chose develops prostate cancer resembling human prostate cancer in distinct stages due to inactivation of endogenous tumor suppressor gene (PTEN) that is frequently deleted in majority of human prostate tumors. Therefore the results obtained in this model will have direct translational application for therapeutic use. These objectives fit well with the program announcement PA-07-362 focusing on the identification and characterization of molecular targets for bioactive food components. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCA) is a major health problem with incidence increasing with age. The goal of this proposal is to test a life-span increasing, cost-effective and non toxic dietary supplement in a preclinical model of PCA targeting novel SIRT1 signaling (associated with increasing life span) for prostate cancer prevention.