Molecular Link Between Metabolic Syndrome and Prostate Cancer

描述(申请人提供)：前列腺癌(PCa)发生在超重或肥胖的患者中与较高的死亡率相关。然而，全身代谢改变和生物侵袭性前列腺癌之间关系的分子基础却知之甚少。代谢综合征(METS)的临床特征是血脂异常、胰岛素抵抗和中心性肥胖等代谢改变，生化特征是能量感受器5‘AMP激活的蛋白激酶(AMPK)失活，主要发生在肝脏和肌肉。我们假设METS患者的前列腺癌是由前列腺癌细胞中AMPK失活驱动的一种独特的分子表型。我们发现甲硫氨酸是侵袭性前列腺癌的风险因素。流行病学研究报告称，使用间接AMPK激活剂二甲双胍可降低糖尿病患者的癌症风险和癌症相关死亡率。此外，我们发现AMPK的直接激活在体外和体内通过抑制新生脂肪生成和较小程度的mTORC1途径来抑制PCA细胞的生长。我们计划剖析前列腺癌中蛋氨酸的全身性生化改变与AMPK失活之间的分子途径。我们正在研究Mets或Mets的遗传易感性是否会导致PCa肿瘤中独特的分子表型。最终目标是确定可能受益于AMPK或其下游效应通路的治疗靶点的PCa患者，这些通路包括但不限于mTOR、蛋白质合成和脂肪生成。为了实现这一目标，我们建议使用包括小鼠遗传学、细胞生物学、生物化学、生物信息学和分子流行病学在内的多学科方法，具体目的如下：目的1.在基因工程细胞和小鼠模型中研究AMPK在前列腺癌发生和发展中的作用；目的2.建立AMPK失活的分子特征，并研究其与人类代谢综合征的关系；目的3.探索前列腺癌与糖尿病/代谢综合征的遗传机制；目的4.评价AMPK失活信号在利用人前列腺癌体外器官型切片培养进行治疗选择方面的潜力。该项目将在蛋氨酸和侵袭性前列腺癌之间建立分子联系，并为AMPK失活的前列腺癌的鉴定提供生物标记物。这些患者在非裔美国人中的比例过高，可能会从针对代谢靶点的新疗法策略中受益。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) arising in overweight or obese patients is associated with higher mortality. The molecular underpinnings of the relationship between systemic metabolic alterations and biologically aggressive PCa, however, are poorly understood. The metabolic syndrome (MetS) is characterized clinically by the combination of metabolic alterations including dyslipidemia, insulin resistance and central obesity, and biochemically by inactivation of the energy sensor 5'AMP-activated protein kinase (AMPK), principally in liver and muscle. We hypothesize that PCa arising in patients with MetS is characterized by a unique molecular phenotype driven by the inactivation of AMPK in prostate tumor cells. We showed that MetS is a risk factor for aggressive prostate cancer. Epidemiological studies have reported reduced cancer risks and cancer related mortality in diabetics using the indirect AMPK activator metformin. In addition, we determined that direct AMPK activation inhibits PCa cell growth in vitro and in vivo via the suppression of de novo lipogenesis and to a lesser extent of the mTORC1 pathway. We plan to dissect the molecular pathways that link systemic biochemical alterations of MetS to AMPK inactivation in prostate tumors. We are looking to see if MetS, or a genetic predisposition to MetS, leads to a unique molecular phenotype in PCa tumors. The ultimate goal is to identify PCa patients that might benefit from therapeutic targeting of AMPK or its downstream effector pathways, which include but may not be limited to mTOR and protein synthesis and lipogenesis. In order to accomplish this, we propose to use a multi-disciplinary approach that includes mouse genetics, cellular biology, biochemistry, bioinformatics and molecular epidemiology, with the following specific aims: Aim 1. To investigate the role of AMPK in prostate cancer onset and progression in genetically engineered cells and mouse models; Aim 2. To develop molecular signatures of AMPK inactivation and study their relationship with the metabolic syndrome in a human population; Aim 3. To explore the genetic mechanism linking prostate cancer to diabetes/metabolic syndrome; and Aim 4. To evaluate the potential of the AMPK inactivation signature in selection of therapeutics utilizing ex-vivo organotypic slice cultures of human prostate cancer. This project will establish a molecular connection between MetS and the aggressive form of PCa that arises in these individuals, and provide a biomarker for the identification of PCa with AMPK inactivation. These patients, over-represented in the African-American population, will likely benefit from novel therapeutics strategies directed at metabolic targets.