Prostate Cancer Prevention by n-3 Unsaturated Fatty Acids

描述（由申请人提供）：流行病学证据强调n-3多不饱和脂肪酸（PUFAs）对前列腺癌发病率的影响。在一项对5万名男性进行的为期12年的前瞻性人群研究中，每周食用三次富含n-3 PUFAs的鱼，可将转移性前列腺癌的风险降低一半。申请人的工作已经确定了EPA抗癌作用的分子机制，主要是海洋n-3 PUFA: EPA引起Ca++-store介导的翻译起始因子elf2 α的磷酸化，从而在起始水平抑制mRNA的翻译。这导致致癌蛋白的优先下调，导致细胞周期停滞在G1期，并增加翻译调节的促凋亡蛋白的表达。每天给药EPA增加了携带人类前列腺原位xenograph肿瘤的小鼠的预期寿命，并使p53 -/小鼠的预期寿命增加了一倍。在前列腺癌细胞、前列腺异种肿瘤和人前列腺中，可以很容易地用抗磷酸化的elf2 α特异性抗体检测到elf2 α的磷酸化，elf2 α是EPA抗癌作用的关键分子介质。因此，磷酸化的elf2 α作为本研究的主要终点，可以作为EPA在前列腺癌中翻译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的饮食具有抗前列腺癌活性，因为它们减少了翻译调节的致癌蛋白的表达，增加了翻译调节的促凋亡蛋白的表达。为了验证这一假设，我们将：1)进行一项前瞻性随机安慰剂对照干预研究，以确定术前每日口服蒸馏油（70% EPA）是否会诱导前列腺肿瘤中elf2 α的磷酸化；2)通过红细胞脂肪酸分析确定日粮脂肪酸组成与前列腺活检elf2 α磷酸化水平和Gleason评分的相关性；3)利用收集到的与10年随访临床数据相关的前列腺肿瘤进行回顾性研究，分析肿瘤中elf2 α磷酸化、Gleason评分与PSA失效时间之间的相关性。作为所有研究的次要终点，我们将把前列腺癌的临床参数与翻译调节的致癌蛋白（如Ras、c-myc和cyclin D1）和促凋亡蛋白（如CHOP）的表达联系起来。这项工作将为促进饮食干预以增加n-3 PUFAs以预防前列腺癌提供强大的细胞和分子基础。

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.