Molecular Link Between Metabolic Syndrome and Prostate Cancer

描述（由申请人提供）：超重或肥胖患者的前列腺癌（PCa）与较高的死亡率相关。然而，系统代谢改变与生物侵袭性前列腺癌之间关系的分子基础尚不清楚。代谢综合征（MetS）的临床特征是代谢改变，包括血脂异常、胰岛素抵抗和中心性肥胖，以及能量传感器5' amp活化蛋白激酶（AMPK）的生化失活，主要发生在肝脏和肌肉。我们假设met患者中出现的PCa具有独特的分子表型，由前列腺肿瘤细胞中AMPK的失活驱动。我们发现met是侵袭性前列腺癌的一个危险因素。流行病学研究报道，使用间接AMPK激活剂二甲双胍可以降低糖尿病患者的癌症风险和癌症相关死亡率。此外，我们确定AMPK的直接激活通过抑制新生脂肪生成和较小程度的mTORC1途径抑制体外和体内PCa细胞的生长。我们计划在前列腺肿瘤中剖析将MetS的系统性生化改变与AMPK失活联系起来的分子途径。我们正在寻找是否MetS，或对MetS的遗传易感性，导致前列腺癌肿瘤中独特的分子表型。最终目标是确定可能受益于治疗靶向AMPK或其下游效应途径的PCa患者，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，具体目标如下：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；目标2。开发AMPK失活的分子特征并研究其与人群代谢综合征的关系；目标3。探讨前列腺癌与糖尿病/代谢综合征的遗传机制；和Aim 4。评估AMPK失活特征在利用人前列腺癌离体器官型切片培养选择治疗方法中的潜力。该项目将建立MetS与这些个体中出现的侵袭性PCa之间的分子联系，并为鉴定AMPK失活的PCa提供生物标志物。这些患者，在非裔美国人人口中占多数，可能会受益于针对代谢目标的新型治疗策略。

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.