Inhibition of Eicosanoids in Prostate Cancer by Fish Oil

鱼油对类二十烷酸对前列腺癌的抑制作用

• 批准号: 7152253
• 负责人: YONG Q CHEN
• 金额: $ 10.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152253
• 关键词: apoptosis; arachidonate; cancer prevention; cell line; cell proliferation; chemoprevention; cyclooxygenase inhibitors; dietary supplements; eicosanoid metabolism; electrospray ionization mass spectrometry; high performance liquid chromatography; ibuprofen; laboratory mouse; lipoxygenase; marine animal oil; molecular oncology; neoplastic cell; neoplastic growth; nutrition aspect of cancer; nutrition related tag; omega 3 fatty acid; prostaglandin E; prostaglandin endoperoxide synthase; prostate neoplasms; radioimmunoassay; receptor binding

We hypothesize that prostate cancer cells metabolize their arachidonic acid (AA) stores via cyclooxygenases (COX), 5-lipoxygenase (LOX), or 15-LOX-1 to prostaglandin (PG)E2, 5-hydroxy-eicosatetraenoate (5-HETE), or 12-HETE, respectively, that the production of one or more of these eicosanoids is essential for prostate cancer cell proliferation, and that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) interfere with the oxygenases to inhibit this proliferation. We have developed a model relevant to these hypotheses. Pten[loxp/loxp]xPB-Cre4 (Pten-/-) mice develop prostate lesions that progress from hyperplasia to cancer. This progression is speeded in mice fed an n-6 diet (rich in AA and AA precursors) and suppressed in mice fed an n-3 diet (rich in EPA and DHA). We will test our hypotheses using human and mouse prostate cells in vitro and our animal model in vivo with three Specific Aims. These Aims are designed to show that: 1) Human prostate cancer cell lines and Pten-/-' mouse prostate cells use 5-LOX, COX-1/2, and/or 15-LOX-1 to make 5-HETE, PGE2, and/or 12-HETE to promote their own proliferation in vitro. 2) EPA and DHA interfere with one or more of the oxygenases to block eicosanoid production and thereby inhibit the proliferation of human prostate cancer cell lines and Pten-/- mouse prostate cells in vitro. 3) The n-3 diet similarly interferes with one or more of the oxygenases to block eicosanoid production and the malignant growth of the prostate gland and thereby improves survival in Pten-/- mice. Previous studies have measured AA metabolites in prostate cancer cell lines in vitro but preloaded the cells with AA to detect the metabolites. AA preloading would pervert any investigation into the effects of EPA, DHA, and the n-3 diet on AA metabolism. We have established a reversed-phase high performance liquid chromatography/electrospray ionization tamdem mass spectroscopy method and with it detected for the first time PGE2, 5-HETE, and 12-HETE in resting PC-3 cells not preloaded with AA. This represents a significant advance that will allow us to characterize the metabolites of AA, EPA, and DHA made by prostate cells and tissues in vitro and in vivo. We are therefore positioned to test our hypotheses and thereby to identify the molecular targets and define the mechanism for the anti-cancerous effects of EPA, DHA, and the fish oil diets which contain these fatty acids.

我们假设前列腺癌细胞通过环氧酶代谢其蛛网膜酸（AA）储存 （COX），5-脂氧合酶（LOX）或15-lox-1至前列腺素（PG）E2，5-羟基 - Eicosatetraenoate（5-HeTe），5-HETE）， 或12-Heeth，其中一种或多种类类生产对于前列腺是必不可少的 癌细胞的增殖，以及eicosapentaenoic酸（EPA）和二十六烯酸（DHA）干扰 用氧酶抑制这种增殖。我们已经开发了与这些假设相关的模型。 PTEN [LOXP/LOXP] XPB-CRE4（PTEN - / - ）小鼠会形成从增生到癌症发展的前列腺病变。这 在喂养N-6饮食（富含AA和AA前体）的小鼠中，进展受到加速 N-3饮食（富含EPA和DHA）。我们将在体外使用人和小鼠前列腺细胞检验假设 我们的动物模型在体内具有三个特定目标。这些目标旨在表明： 1）人类前列腺癌细胞系和PTEN - / - '小鼠前列腺细胞使用5-lox，Cox-1/2和/或15-lox-1 制作5-HETE，PGE2和/或12-HETE以在体外促进自己的扩散。 2）EPA和DHA干扰一种或多种氧合酶，以阻止类eicosanoid的产生 在体外抑制人前列腺癌细胞系的增殖和PTEN - / - 小鼠前列腺细胞。 3）N-3饮食类似地干扰了一种或多种氧合酶，以阻止类固醇生产和 前列腺的恶性生长，从而改善了PTEN - / - 小鼠的生存。 先前的研究已经在体外测量了前列腺癌细胞系中的AA代谢产物，但预加载了细胞。 使用AA检测代谢物。 AA预加载将使对EPA的影响进行任何调查， DHA，以及AA代谢的N-3饮食。我们已经建立了相反的高性能液体 色谱/电喷雾电离TAMDEM质谱法，并检测到第一个 时间PGE2，5-HETE和12-HETE在未用AA预加载的静止PC-3细胞中。这代表着重要的 前进将使我们能够表征前列腺细胞和前列腺和DHA的代谢产物的代谢物和 在体外和体内组织。因此，我们有定位来检验我们的假设，从而确定 分子靶标并定义EPA，DHA和鱼油抗癌作用的机制 含有这些脂肪酸的饮食。