Phospholipid Signaling in Fish oil-induced Growth Inhibition of Prostate Cancer

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

For more than 2 decades, epidemiologic studies have been reported on the effect of dietary fat on the risk of[unreadable] prostate cancer. Experimental data indicate that n-3 polyunsaturated fatty acids (PUFAs) inhibit whereas n-6[unreadable] PUFAs stimulate prostate cancer cell growth. However, the mechanism of PUFA's effect is unknown.[unreadable] n-3 and n-6 PUFAs are essential fatty acids and necessary for survival. Mammals cannot synthesize these[unreadable] fatty acids cte novo, neither can convert n-6 to n-3 or vice versa. Therefore they have to be taken in from diet.[unreadable] Fish oil is a rich source of n-3 polyunsaturated fatty acids. We hypothesize that n-3 PUFAs incorporate into[unreadable] the sn-2 position of phospholipids, and the n-3 PUFA-enriched phosphoinositides affect the Akt signaling[unreadable] pathway, regulate expression of genes resulting in prostate cell growth inhibition. In this project, we will study[unreadable] the suppression of prostate cancer progression by n-3 fatty acid enriched diet and its mechanism of action.[unreadable] Our specific aims are: Determine the effect of n-3 fatty acids on prostate cancer proliferation, progression[unreadable] and metastasis. We will assess the n-3 diet on prostate cancer proliferation, histological progression,[unreadable] expression of biomarkers (genes, proteins and lipids), survival and metastasis; Determine whether the timing[unreadable] of n-3 fatty acid intake differentially affects prostate cancer. We will determine whether early- and/or lateintake[unreadable] will have a similar effect on prostate cancer to life-long intake of n-3 fatty acids. Clinically, it is[unreadable] important to know whether childhood intake of n-3 fatty acids and whether n-3 fatty acids supplementation[unreadable] after the development of prostate cancer are beneficial; Determine the effect of n-3 fatty acids on the[unreadable] localization of phosphoinositides and on the Akt signaling pathway. We will determine whether n-3 fatty acid[unreadable] containing PIPs affect Pdk and Akt protein localization, activation and downstream signaling.[unreadable] We take advantage of our strengths of in vivo and in vitro, mouse and human model systems. For the first[unreadable] time, molecular changes (mRNA and lipid) associated with fish oil diet in the prostate will be[unreadable] comprehensively and systematically analyzed. In addition, conventional pathway dissection approach will[unreadable] also be applied to study the mechanism of action of fish oil on prostate cancer.