Cholesterol and Prostate Cancer Progression

描述（由申请人提供）： 虽然前列腺癌（PCa）仍然是美国男性癌症死亡的主要原因之一，但影响疾病进展的特定营养因素及其潜在作用机制在很大程度上尚不清楚。该项目测试的假设，血清胆固醇和膜胆固醇，通过其在调节脂筏膜结构域的大小和复杂性的作用，影响参数的PCa在体外和体内的进展。本申请通过直接评价饮食胆固醇对前列腺肿瘤进展的影响以及膜胆固醇调节ErbB/PI 3 K/Akt抗凋亡信号传导轴（在前列腺肿瘤细胞中组成性运行的关键细胞存活途径）的能力来响应RFA。在这些研究中，我们将研究富含胆固醇的脂筏信号传导复合物在协调和调节ErbB受体家族分布、二聚化和激活、PI 3激酶分布和激活以及Akt亚型分布和激活中的作用。我们将确定膜胆固醇调节对这些信号分子和前列腺肿瘤细胞存活的影响。我们将使用人类肿瘤细胞进展的小鼠模型以及两个本地PCa小鼠模型研究饮食胆固醇对体内前列腺肿瘤进展的影响。我们将测试高水平的饮食胆固醇是否会导致PIN转化为坦率的癌症，加速前列腺肿瘤的生长并促进转移。我们将确定高水平的饮食胆固醇是否会导致前列腺肿瘤中的胆固醇积累，并影响脂筏结构域的形式和功能。这些关于饮食和膜胆固醇对PCa疾病进展的作用的假设驱动的机制研究可能提示用于治疗和管理该疾病的新疗法，例如使用HMG-CoA还原酶抑制剂药物或使用低胆固醇饮食。此外，这些研究也有可能确定新的药物靶点。

DESCRIPTION (provided by applicant): Although prostate cancer (PCa) remains one of the leading causes of death from cancer in American men, the specific nutritional factors affecting disease progression and their potential mechanisms of action are largely unknown. This project tests the hypothesis that serum cholesterol and membrane cholesterol, through their roles in regulating the size and complexity of lipid raft membrane domains, affect parameters of PCa progression in vitro and in vivo. This application responds to the RFA by directly evaluating the effect of dietary cholesterol on prostate tumor progression and the ability of membrane cholesterol to regulate the ErbB/PI3K/Akt anti-apoptotic signaling axis, a critical cell survival pathways operating constitutively in prostate tumor cells. In these studies we will examine the role of cholesterol-rich lipid raft signaling complexes in orchestrating and regulating ErbB receptor family distribution, dimerization and activation, PI3 kinase distribution and activation, and Akt isoform distribution and activation. We will determine the effect of membrane cholesterol modulation on these signaling molecules and on prostate tumor cell survival. We will study the effect of dietary cholesterol on prostate tumor progression in vivo using a murine model of human tumor cell progression, as well as two autochthonous PCa mouse models. We will test whether high levels of dietary cholesterol cause PIN to convert to frank cancer, to accelerate the growth of prostate tumors and to promote metastasis. We will determine whether high levels of dietary cholesterol cause cholesterol accumulation in prostate tumors and affect the form and function of lipid raft domains. These hypothesis driven, mechanistic studies on the role of dietary and membrane cholesterol on PCa disease progression may suggest new therapies for the treatment and management of the disease, such as the use of HMG-CoA reductase inhibitor drugs or the use of low cholesterol diets. Further, these studies also have the potential to identify new drug targets.