Epidemiological evidence highlights the influence of n-3 polyunsaturated fatty acids (PUFAs) on the incidence of prostate cancer. In a 12-year prospective population study of about 50,000 men, consumption of fish, a rich source of n-3 PUFAs, three times per week halved the risk of metastatic prostate cancer. Work by the applicants has identified the molecular mechanism of the anti-cancer effect of EPA, the main marine n-3 PUFA: EPA causes Ca++-stores mediated phosphorylation of the translation initiation factor elF2alpha and thereby inhibition of mRNA translation at the initiation level. This results in preferential downregulation of oncogenic proteins leading to cell cycle arrest in the G1 phase and to increased expression of translationally regulated pro-apoptotic proteins. Daily administration of EPA increased the life expectancy of mice bearing orthotopic xenograph human prostate tumors, and doubled the life expectancy of p53 -/ mice. Phosphorylation of elF2alpha, the critical molecular mediator of the anti-cancer action of EPA, can be readily detected with anti-phosphorylated elF2alpha-specific antibodies in prostate cancer cells, in prostate xenograph tumors and in the human prostate. Thus, phosphorylated elF2alpha, the primary endpoint of the studies in this application, can be used as a molecular biomarker of the translation-initiation inhibitory activity of EPA in prostate cancers. Our hypothesis is that consumption of diets rich in marine n-3 PUFAs exerts anti-prostate cancer activity because they reduce the expression of translationally regulated oncogenic proteins and increase expression of translationally regulated pro-apoptotic proteins. To test this hypothesis, we will: 1) conduct a prospective randomized placebo-controlled intervention study to determine whether oral daily administration of distilled fish oil (70% EPA) before surgery induces phosphorylation of elF2alpha in prostate tumors; 2) determine the correlation between the fatty acid composition of the diet, as determined by fatty acid analysis of red blood cells, with the levels of elF2alpha phosphorylation and Gleason score in prostate biopsies; and 3) conduct a retrospective study using an available collection of prostate tumors linked to 10 years follow-up clinical data to analyze the correlation between elF2alpha phosphorylation in the tumors, their Gleason score and the time to PSA failure. As secondary endpoint in all studies we will correlate both clinical parameters of prostate cancer with the expression of translationally regulated oncogenic proteins such as Ras, c-myc and cyclin D1, and of pro-apoptotic proteins such as CHOP. This effort will provide a strong cellular and molecular basis for the promotion of dietary interventions to increase n-3 PUFAs for the prevention of prostate cancer. ? ?
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