Cholesterol and Prostate Cancer Progression

描述(由申请人提供)： 尽管前列腺癌(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的作用机制在很大程度上尚不清楚。本项目验证了这一假说，即血清胆固醇和膜胆固醇通过调节脂筏膜结构域的大小和复杂性，在体外和体内影响PCA进展的参数。这项应用通过直接评估膳食胆固醇对前列腺癌进展的影响以及膜胆固醇调节ErbB/PI3K/Akt抗凋亡信号轴的能力来响应RFA，ErbB/PI3K/Akt是前列腺癌细胞中一个关键的细胞生存途径。在这些研究中，我们将研究富含胆固醇的脂类RAFT信号复合体在协调和调节ErbB受体家族分布、二聚化和激活、PI3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和两个固有的前列腺癌小鼠模型来研究饮食胆固醇对体内前列腺癌进展的影响。我们将测试高水平的饮食胆固醇是否会导致PIN转化为直肠癌，加速前列腺癌的生长，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癌中胆固醇的积聚，并影响脂筏结构域的形式和功能。这些假设驱动的、关于饮食和膜胆固醇在前列腺癌疾病进展中的作用的机械性研究可能会为疾病的治疗和管理提供新的治疗方法，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，这些研究还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.