Metabolic Syndrome, Fatty Acid Synthesis and Prostate Cancer

描述（由申请人提供）：脂肪酸合成在肿瘤组织中以非常高的速率发生，如超过半个世纪前首次证实的。重要的是，14 C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。过表达FAS的前列腺癌（PCa）表现出侵袭性生物学行为，表明FAS过表达赋予选择性生长优势。我们已经证明，在永生化的人前列腺上皮细胞中FAS表达失调，并作为针对小鼠前列腺的转基因，分别导致浸润性腺癌和前列腺上皮内瘤形成。 代谢综合征（MS）以胰岛素抵抗、向心性肥胖和高血压为特征，与主能量传感器激酶AMPK的失活相关，并且最近在大型流行病学研究中与较高的PCa发病率相关。AMPK在被激活时抑制FAS活性，从而消除其致癌特性。我们的初步数据表明，血清脂联素（AMPK的内源性激活剂）水平低，显著预测PCa存活率低。总之，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。 该提议的首要假设是，FAS过表达是持续AMPK抑制的效应子致瘤途径。为了验证这一假设，我们将利用多学科的方法，结合细胞生物学，动物模型研究，基于组织的方法和生殖细胞多态性与PCa进展的大型，注释的PCa患者队列。 具体而言，我们将a）确定AMP激酶是否是抑制FAS活性的分子靶标; B）评估PCa中FAS介导的致癌性的选定潜在机制，例如通过关键调节基因的棕榈酰化激活途径c）评估编码AMPK、FAS、使用单倍型标记单核苷酸多态性（SNPs），它们的调节基因是前列腺癌进展和存活的预测因子;和d）将FAS/AMPK轴的功能状态与来自相同组群的组织中的代谢综合征相关联。 所提出的实验将确立FAS作为前列腺癌中的代谢致癌基因，将通过主能量调节激酶AMPK巩固代谢综合征、肥胖和前列腺癌之间的联系，并确立FAS及其调节因子/效应因子作为PCa中的治疗靶点。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。从这项提案中获得的数据，包括流行病学，小鼠模型和人类肿瘤分析，将提供长期寻求的饮食，肥胖和前列腺癌之间的分子联系。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.