Molecular Link Between Metabolic Syndrome and Prostate Cancer

代谢综合征与前列腺癌之间的分子联系

• 批准号: 8761515
• 负责人: Massimo Loda
• 金额: $ 37.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761515
• 关键词: 5' -AMP-activated protein kinase; Ablation; Advanced Malignant Neoplasm; African American; Biochemical; Biochemistry and Cellular Biology; Bioinformatics; Biological Markers; Biopsy; Cancer Cell Growth; Cancer Patient; Cells; Central obesity; Clinical Data; Complex; Data; Databases; Diabetes Mellitus; Diagnosis; Dyslipidemias; Elements; Enzymes; Epidemiologic Studies; Fatty-acid synthase; Gene Expression; Genetic; Genetic Engineering; Genetic Predisposition to Disease; Goals; Grant; Growth; Human; In Vitro; Individual; Insulin Resistance; Link; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Metformin; Modeling; Molecular; Molecular Epidemiology; Molecular Profiling; Mus; Muscle; Obesity; Overweight; Pathway interactions; Patients; Pharmacodynamics; Phenotype; Population; Prostate; Prostatic; Prostatic Neoplasms; Protein Biosynthesis; Radical Prostatectomy; Reporting; Risk; Risk Factors; Role; Signal Transduction; Slice; Specimen; Therapeutic; Therapeutic Intervention; Time; Tissues; advanced disease; base; cancer risk; cohort; diabetes risk; diabetic; energy balance; genetic variant; genetically modified cells; in vivo; inhibitor/antagonist; lipid biosynthesis; mTOR protein; metabolomics; molecular phenotype; mortality; mouse model; neoplastic cell; novel; novel therapeutics; prostate cancer cell; protein profiling; public health relevance; response marker; risk variant; sensor; therapeutic target; tumor; tumorigenesis

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.

描述（由申请人提供）：超重或肥胖患者发生的前列腺癌（PCa）与较高的死亡率相关。然而，人们对全身代谢改变和前列腺癌生物侵袭性之间关系的分子基础知之甚少。代谢综合征（MetS）的临床特征是代谢改变的组合，包括血脂异常、胰岛素抵抗和向心性肥胖，生化特征是能量传感器5'AMP激活蛋白激酶（AMPK）（主要在肝脏和肌肉中）失活。我们假设 MetS 患者出现的 PCa 具有独特的分子表型，该分子表型是由前列腺肿瘤细胞中 AMPK 失活驱动的。我们证明 MetS 是侵袭性前列腺癌的危险因素。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，我们确定 AMPK 的直接激活通过抑制从头脂肪生成以及较小程度的 mTORC1 途径来抑制体外和体内 PCa 细胞生长。我们计划剖析将 MetS 的全身生化改变与前列腺肿瘤中 AMPK 失活联系起来的分子途径。我们正在研究 MetS 或 MetS 的遗传倾向是否会导致 PCa 肿瘤出现独特的分子表型。最终目标是确定可能受益于 AMPK 或其下游效应途径（包括但可能不限于 mTOR 以及蛋白质合成和脂肪生成）的治疗靶向的 PCa 患者。为了实现这一目标，我们建议采用多学科方法，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，具体目标如下： 目标 1. 研究 AMPK 在前列腺癌发病和发生中的作用。基因工程细胞和小鼠模型的进展；目标 2. 开发 AMPK 失活的分子特征并研究它们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；目标 4. 评估 AMPK 失活特征在利用人前列腺癌离体器官切片培养物选择治疗方法中的潜力。该项目将在 MetS 与这些个体中出现的侵袭性 PCa 之间建立分子联系，并为识别具有 AMPK 失活的 PCa 提供生物标志物。这些患者在非裔美国人群体中所占比例过高，可能会受益于针对代谢目标的新型治疗策略。