Dietary Prevention of Hormone Refractory Prostate Cancer

描述（由申请人提供）： 起源于雄激素靶组织（如前列腺）的癌症依赖于雄激素生长。雄激素通过结合并激活雄激素受体（AR）来表现其作用。抗雄激素治疗抑制前列腺癌细胞的生长。然而，大多数前列腺癌最终发展为雄激素非依赖性表型，并对抗激素治疗产生抗性。Akt激酶在体外使AR磷酸化，并允许在不存在雄激素的情况下激活AR。还观察到Akt过度活跃足以将AR阳性前列腺癌细胞从对化疗敏感的表型转化为耐药表型。欧米茄-3脂肪酸长期以来被认为是动物模型中有效的抗肿瘤药物，但它们表现这些作用的机制仍不清楚。在乳腺癌模型中，我们已经证明omega-3脂肪酸抑制Akt活性，表明这些饮食成分影响肿瘤生长的一种机制是通过Akt途径阻断促有丝分裂信号传导。根据这些结果，我们假设：1）ω-3脂肪酸能够抑制AR阳性前列腺癌细胞中Akt的有丝分裂原刺激激活。2)ω-3脂肪酸对Akt的抑制消除了Akt依赖性的从对糖尿病应答的表型到糖尿病难治的表型的进展。我们将通过首先研究Akt及其下游靶点对AR阳性、雄激素依赖性LnCaP前列腺癌细胞系中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及其各自下游靶标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通过ω-3脂肪酸治疗抑制Akt活性是否阻止雄激素非依赖性状态的进展。这项研究应用的结果将为进一步研究使用饮食干预靶向特定分子靶点预防表型特异性癌症奠定基础。

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.