Metabolic Syndrome, Fatty Acid Synthesis and Prostate Cancer

描述(由申请人提供)：半个多世纪前首次证明，脂肪酸在肿瘤组织中的合成速度非常快。重要的是，14C葡萄糖掺入研究表明，在肿瘤细胞中，尽管有足够的营养供应，但几乎所有的脂肪酸都来自从头合成。前列腺癌(Pca)过表达Fas表现出侵袭性的生物学行为，提示Fas过表达具有选择性生长优势。我们已经证明，在永生化的人前列腺上皮细胞中，Fas表达的解除调控和作为针对小鼠前列腺的转基因分别导致侵袭性腺癌和前列腺上皮内瘤变。 代谢综合征(MS)的特征是胰岛素抵抗、中心性肥胖和高血压，与主能量感受器激酶AMPK的失活有关，最近在大型流行病学研究中与较高的PCa发病率有关。AMPK被激活时，会抑制Fas的活性，从而取消其致癌特性。我们的初步数据显示，低水平的血清脂联素，AMPK的内源性激活剂，显著预示着较差的PCa存活率。综上所述，这些结果强烈表明代谢综合征、AMPK、Fas和PCa之间存在生物学联系。 这一建议的主要假设是，Fas的过度表达是持续抑制AMPK的效应致瘤途径。为了验证这一假设，我们将利用一种多学科的方法，结合细胞生物学、动物模型研究、基于组织的方法以及胚系多态与PCa进展的相关性，在大量的有注释的PCa患者队列中进行研究。 具体地说，我们将a)确定AMP激酶是否是抑制Fas活性的分子靶点；b)评估Fas介导的致癌作用的选定的潜在机制，例如通过关键调控基因的棕榈酰化激活通路；c)利用单倍型标记单核苷酸多态(SNPs)评估编码AMPK、Fas及其调控基因的基因座的遗传变异是否预测前列腺癌的进展和生存；以及d)将Fas/AMPK轴的功能状态与同一队列组织中的代谢综合征联系起来。 建议的实验将建立Fas作为前列腺癌的代谢癌基因，将通过主要的能量调节蛋白激酶AMPK巩固代谢综合征、肥胖和前列腺癌之间的联系，并建立Fas及其调节/效应因子作为前列腺癌的治疗靶点。公共卫生相关性：在这项提案中，我们正在研究关键代谢酶在前列腺癌中的作用。我们特别关注一种代谢酶，它对控制人类肥胖和血糖控制至关重要。这项提议产生的数据包括流行病学、小鼠模型和人类肿瘤分析，将提供饮食、肥胖和前列腺癌之间长期寻求的分子联系。此外，这项研究可能会导致这种疾病的新治疗方法。

DESCRIPTION (provided by applicant): Fatty acids synthesis occurs at very high rates in tumor tissues, as first demonstrated more than half a century ago. Importantly, 14C glucose incorporation studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply. Prostate adenocarcinomas (PCa) overexpressing FAS display aggressive biologic behavior, suggesting that FAS overexpression confers a selective growth advantage. We have demonstrated that deregulated FAS expression in immortalized human prostate epithelial cells and as a transgene directed to the murine prostate results in invasive adenocarcinoma and prostatic intraepithelial neoplasia, respectively. The metabolic syndrome (MS), characterized by insulin resistance, central obesity and hypertension, is associated with inactivation of the master energy-sensor kinase AMPK and has recently been related to higher PCa incidence in large epidemiological studies. AMPK, when activated, inhibits FAS activity abolishing its oncogenic properties. Our preliminary data demonstrate that low serum levels of adiponectin, an endogenous activator of AMPK, significantly predict poor PCa survival. Taken together, these results strongly suggest a biological link between the metabolic syndrome, AMPK, FAS and PCa. The overarching hypothesis of this proposal is that FAS overexpression is the effector tumorigenic pathway of sustained AMPK inhibition. To validate this hypothesis, we will utilize a multidisciplinary approach that combines cell biology, animal model studies, tissue-based approaches and germline polymorphism correlations with PCa progression in large, annotated cohorts of PCa patients. Specifically, we will a) determine whether AMP kinase is a molecular target for inhibiting FAS activity; b) assess selected potential mechanisms of FAS mediated oncogenicity in PCa such as activation of pathways by palmitoylation of key regulatory genes c) assess whether genetic variations in the loci encoding AMPK, FAS, and their regulatory genes are predictors of prostate cancer progression and survival using haplotype tagging single nucleotide polymorphisms (SNPs); and d) relate the functional status of the FAS/AMPK axis to the metabolic syndrome in tissues from the same cohorts. The experiments proposed will establish FAS as a metabolic oncogene in prostate cancer, will solidify the link between the metabolic syndrome, obesity and prostate cancer through the master energy regulator kinase AMPK and establish FAS, and its regulators/effectors, as therapeutic targets in PCa. PUBLIC HEALTH RELEVANCE: In this proposal we are studying the role of key metabolic enzymes in prostate cancer. We are specifically focusing on a metabolic enzyme which is central to the control of obesity and blood glucose control in humans. The data resulting from this proposal, which includes epidemiologic, mouse model and human tumor analyses, will provide the long sought molecular link between diet, obesity and prostate cancer. In addition, this research that will likely results in novel therapeutic approaches in this disease.