Metabolic Syndrome, Fatty Acid Synthesis and Prostate Cancer

代谢综合征、脂肪酸合成和前列腺癌

基本信息

批准号：
7529009
负责人：
Massimo Loda
金额：
$ 35.03万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529009
关键词：
1-Phosphatidylinositol 3-Kinase AMP-activated protein kinase kinase Adenocarcinoma Animal Model Apoptosis Behavior Biological Biological Assay Blood Glucose Cancer Patient Cells Cellular biology Central obesity DNA Data Databases Diet Disease Enzymes Epidemiologic Studies Epithelial Cells Fatty Acids Fatty-acid synthase Genes Genetic Polymorphism Genetic Variation Glucose Growth Haplotypes Human Hypertension Incidence Insulin Resistance Invasive Link Lipids Malignant neoplasm of prostate Mediating Metabolic Metabolic syndrome Metastatic to Mitogen-Activated Protein Kinase Kinases Mitogens Modification Molecular Molecular Target Mus Nutritional Obesity Oncogenes Oncogenic Palmitic Acids Pathway interactions Patients Property Prostate Prostate Adenocarcinoma Prostatic Intraepithelial Neoplasias Protein Overexpression Proteins Public Health Rate Regulation Regulator Genes Research Role Serum Signal Transduction Pathway Single Nucleotide Polymorphism Testing Tissues Transgenes Tumor Tissue Variant Xenograft Model adenylate kinase adiponectin base blood glucose regulation bone cohort functional status in vivo interdisciplinary approach mouse model myristoylation neoplastic cell novel therapeutics palmitoylation research study sensor therapeutic target tumor tumor progression tumorigenic

项目摘要

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.

描述（由申请人提供）：正如半个多世纪前首次证明的那样，肿瘤组织中的脂肪酸合成率非常高。重要的是，14C葡萄糖掺入研究表明，在肿瘤细胞中，尽管营养供应充足，但几乎所有脂肪酸都来自从头合成。过度表达 FAS 的前列腺腺癌 (PCa) 表现出侵袭性生物学行为，表明 FAS 过度表达具有选择性生长优势。我们已经证明，永生化人前列腺上皮细胞中FAS表达失调以及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) 以胰岛素抵抗、中心性肥胖和高血压为特征，与主能量传感器激酶 AMPK 失活有关，最近在大型流行病学研究中发现与 PCa 发病率较高有关。 AMPK 激活后会抑制 FAS 活性，消除其致癌特性。我们的初步数据表明，低血清脂联素（AMPK 的内源性激活剂）水平可显着预测 PCa 存活率较差。总而言之，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。该提议的总体假设是 FAS 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，我们将利用多学科方法，结合细胞生物学、动物模型研究、基于组织的方法以及大型、有注释的 PCa 患者群体中种系多态性与 PCa 进展的相关性。具体来说，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 FAS 介导的 PCa 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) 使用以下方法评估编码 AMPK、FAS 及其调节基因的基因座中的遗传变异是否是前列腺癌进展和生存的预测因素单倍型标记单核苷酸多态性 (SNP)； d) 将 FAS/AMPK 轴的功能状态与来自同一队列的组织中的代谢综合征联系起来。拟议的实验将确定 FAS 作为前列腺癌的代谢癌基因，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，并将 FAS 及其调节器/效应器确定为 PCa 的治疗靶点。公共健康相关性：在本提案中，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，它对于控制人类肥胖和血糖控制至关重要。该提案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找的分子联系。此外，这项研究可能会产生治疗这种疾病的新方法。