Prostate Cancer Prevention by n-3 Unsaturated Fatty Acids

描述（由申请方提供）：流行病学证据强调了n-3多不饱和脂肪酸（PUFA）对前列腺癌发病率的影响。在一项为期12年的前瞻性人群研究中，约有50，000名男性，每周三次食用鱼，一种丰富的n-3 PUFA来源，转移性前列腺癌的风险减半。本申请人的工作已经确定了EPA（主要的海洋n-3 PUFA）抗癌作用的分子机制：EPA导致翻译起始因子eIF 2 α的Ca++-储存介导的磷酸化，从而在起始水平抑制mRNA翻译。这导致致癌蛋白的优先下调，从而导致细胞周期停滞在G1期，并增加了诱导调节的促凋亡蛋白的表达。EPA的每日给药增加了原位异种移植人前列腺肿瘤小鼠的预期寿命，并使p53 -/小鼠的预期寿命加倍。EPA抗癌作用的关键分子介体eIF 2 α的磷酸化可以在前列腺癌细胞、前列腺异种移植肿瘤和人前列腺中用抗磷酸化eIF 2 α特异性抗体容易地检测。因此，磷酸化eIF 2 α（本申请中研究的主要终点）可用作前列腺癌中EPA的预防起始抑制活性的分子生物标志物。我们的假设是，食用富含海洋n-3 PUFAs的饮食发挥抗前列腺癌活性，因为它们减少了调节性致癌蛋白的表达，并增加了调节性促凋亡蛋白的表达。1）进行前瞻性随机安慰剂对照干预研究，以确定手术前每日口服蒸馏鱼油（70%EPA）是否诱导前列腺肿瘤中eIF 2 α的磷酸化; 2）确定饮食的脂肪酸组成之间的相关性，如通过红细胞的脂肪酸分析所确定的，与前列腺活组织检查中eIF 2 α磷酸化水平和Gleason评分相关;和3）使用与10年随访临床数据相关的前列腺肿瘤的可用集合进行回顾性研究，以分析肿瘤中eIF 2 α磷酸化、其Gleason评分和PSA失败时间之间的相关性。作为所有研究的次要终点，我们将前列腺癌的临床参数与凋亡调节的致癌蛋白（如Ras、c-myc和细胞周期蛋白D1）和促凋亡蛋白（如CHOP）的表达相关联。这项工作将为促进饮食干预以增加n-3 PUFA预防前列腺癌提供强有力的细胞和分子基础。

DESCRIPTION (provided by applicant): 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.