Dietary Prevention of Hormone Refractory Prostate Cancer

激素难治性前列腺癌的饮食预防

• 批准号: 6803605
• 负责人: LINDA A DEGRAFFENRIED
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803605
• 关键词: androgen receptor; cancer prevention; carcinogenesis inhibitor; cell growth regulation; cell line; clinical research; enzyme activity; hormone related neoplasm /cancer; mitogen activated protein kinase; neoplastic growth; nutrient interaction; nutrition related neoplasm /cancer; nutrition related tag; omega 3 fatty acid; prostate neoplasms; serine threonine protein kinase

DESCRIPTION (provided by applicant): Cancers originating from androgen-target tissues, such as prostate, are dependent on androgens for growth. Androgens manifest their effects by binding to and activating the androgen receptor (AR). Anti-androgen treatment inhibits the growth of prostate cancer cells. However, most prostate cancers eventually develop an androgen-independent phenotype and become resistant to anti-hormone therapy. The Akt kinase phosphorylates the AR in vitro and permits activation of the AR in the absence of androgen. It has also been observed that Akt hyperactivity is sufficient to convert AR-positive prostate cancer cells from the hormonesensitive to the resistant phenotype. Omega-3 fatty acids have long been known as potent anti-tumor agents in animal models, but the mechanisms by which they manifest these effects remain unclear. In a breast cancer model, we have demonstrated that omega-3 fatty acids inhibit Akt activity, suggesting that one mechanism by which these dietary components affect tumor growth is by blocking mitogenic signaling through the Akt pathway. From these results we hypothesize that: 1) omega-3 fatty acids are able to inhibit mitogenstimulated activation of Akt in AR-positive prostate cancer cells. 2) inhibition of Akt by omega-3 fatty acids abrogates the Akt-dependent progression from a hormone-responsive to hormone-refractory phenotype. We will address these hypotheses by first investigating the response of Akt and its downstream targets to treatment with omega-3 fatty acids in the AR-positive, androgen-dependent LnCaP prostate cancer cell line. We will assess kinase activity, and evaluate alterations in expression levels and phosphorylation statuses of both Akt and the AR as well as their respective downstream targets. We will then use an in vitro model of androgen ablation to determine whether inhibition of Akt activity by treatment with omega-3 fatty acids prevents the progression to the androgen-independent state. The results from this research application will lay the foundation for further studies investigating the use of dietary intervention to target specific molecular targets for the prevention of phenotype-specific cancers.

描述(由申请人提供)： 起源于雄激素靶组织的癌症，如前列腺癌，依赖于雄激素的生长。雄激素通过与雄激素受体(AR)结合和激活来显示其作用。抗雄激素治疗抑制了前列腺癌细胞的生长。然而，大多数前列腺癌最终形成雄激素非依赖性表型，并对抗激素治疗产生抗药性。Akt激酶在体外使AR磷酸化，并允许在没有雄激素的情况下激活AR。还观察到Akt的过度活性足以将AR阳性的前列腺癌细胞从激素敏感表型转变为耐药表型。在动物模型中，omega-3脂肪酸长期以来一直被认为是有效的抗肿瘤药物，但它们显示这些作用的机制尚不清楚。在乳腺癌模型中，我们已经证明omega-3脂肪酸抑制Akt活性，这表明这些饮食成分影响肿瘤生长的一个机制是通过Akt途径阻止有丝分裂信号。根据这些结果，我们假设：1)omega-3脂肪酸能够抑制AR阳性前列腺癌细胞中有丝分裂刺激的Akt的激活。2)omega-3脂肪酸对Akt的抑制作用阻断了Akt依赖从激素反应到激素不耐受的过程。我们将通过首先研究Akt及其下游靶点在AR阳性、雄激素依赖的LNCaP前列腺癌细胞系中对omega-3脂肪酸治疗的反应来解决这些假设。我们将评估激酶活性，并评估Akt和AR及其各自下游靶点的表达水平和磷酸化状态的变化。然后，我们将使用雄激素消融的体外模型来确定用omega-3脂肪酸治疗抑制Akt活性是否可以防止进展到雄激素非依赖性状态。这项研究应用的结果将为进一步研究利用饮食干预来针对特定的分子靶点预防表型特异性癌症奠定基础。