The Effect of Diet and Nutrients on the Progression and Treatment of Prostate Can

饮食和营养素对前列腺疾病进展和治疗的影响

• 批准号: 7739860
• 负责人: GEORGE THOMAS
• 金额: $ 62.65万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739860
• 关键词: Branched-Chain Amino Acids; Caloric Restriction; Cancer Biology; Cessation of life; Chemoprevention; Chemotherapy-Oncologic Procedure; Cholesterol; Cohort Studies; Development; Diagnosis; Diet; Energy Intake; Epidemiologic Studies; Fatty acid glycerol esters; Feedback; Genes; Genetically Engineered Mouse; Human; Incidence; Insulin; Knowledge; Lesion; Link; Low Density Lipoprotein Receptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Metformin; Modeling; Molecular; Morbidity - disease rate; Nutrient; Obesity; PTEN gene; Pathway interactions; Prevalence; Process; Production; Prostate; Protocols documentation; Regulation; Resolution; Risk Factors; Role; STK11 gene; Signal Pathway; Signal Transduction; Sirolimus; TSC1/2 gene; Testing; Therapeutic; Tumor Suppressor Proteins; United States; base; cell growth; design; dietary constituent; dietary excess; hypercholesterolemia; isoprenoid; ketogenic diet; male; member; men; mouse model; novel therapeutic intervention; obesity risk; prevent; prospective; research study; response; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is among the leading causes of male cancer-related morbidity and death, second only to lung cancer, representing approximately 10% of all cancer deaths among men in the United States. Prospective cohort studies have shown a statistically significant positive association between obesity and the risk of death from PCa. Consistent with these observations, it has been noted that caloric restriction acts to prevent cancer progression. It was initially thought that the effects of caloric restriction on tumor progression were a secondary response to decreased cell growth; however, it is increasingly being recognized that this process actually impinges on key intracellular signaling pathways, particularly the insulin-IGFI and nutrient- mediated PI3K/ mTORCI signaling pathway, which is opposed by a large number of tumor suppressors including PTEN, TSC1/2, NF1, LKB1, 4E-BP1, PDCD4, and PML. Clearly, further resolution of the molecular mechanisms linking obesity to PCa cannot rely on epidemiological studies alone, but will require the use of mouse models that integrate knowledge obtained from human cancer studies. The project proposed here will examine the role of diet in PCa at a cellular and molecular level by using genetically engineered mice that harbor a specific lesion in the Pten gene. This model will be used in the following experiments: (i) determine the impact of a high-fat diet, ketogenic diet, and dietary constituents or caloric intake in PCa development; (ii) test the hypothesis that hypercholesterolemia promotes PCa progression and that it is related to dysfunctional feedback regulation of the low-density lipoprotein (LDL) receptor, and assess the influence of endogenous production of cholesterol and isoprenoids on cancer progression; (iii) test the effect of excess dietary branched-chain amino acids on PCa progression and the role of mTORCI signaling in this response, and determine whether the effect of caloric restriction on PCa is recapitulated by rapamycin and metformin; (iv) ascertain the mechanism of AMPK pathway regulation by PML in PCa and the therapeutic implications of the PML-AMPK pathway in PCa by employing established PCa chemotherapy and chemoprevention protocols. This timely study in cancer biology will be directed by present members of the NCI-MMHCC and the NIDDK-MMPC. RELEVANCE: Over the course of a lifetime, one in six men in the United States will be diagnosed with prostate cancer. Multiple factors contribute to the high incidence and prevalence of prostate cancer. Among these, obesity is an increasingly important risk factor. This project will examine the role of diet in the progression of prostate cancer and as an avenue for designing new therapeutic approaches based on existing mouse models.

描述（由申请人提供）：前列腺癌（PCa）是男性癌症相关发病率和死亡的主要原因之一，仅次于肺癌，占美国男性所有癌症死亡的约10%。前瞻性队列研究显示，肥胖与PCa死亡风险之间存在统计学显著正相关。与这些观察结果一致，已经注意到热量限制可以防止癌症进展。最初认为热量限制对肿瘤进展的影响是对细胞生长减少的继发反应;然而，越来越多的人认识到，该过程实际上影响关键的细胞内信号传导途径，特别是胰岛素-IGFI和营养物介导的PI 3 K/ mTORCI信号传导途径，其被大量的肿瘤抑制因子（包括PTEN，TSC 1/2，NF 1，LKB 1，4 E-BP 1、PDCD 4和PML。显然，进一步解决肥胖与PCa相关的分子机制不能仅仅依靠流行病学研究，而需要使用整合了人类癌症研究知识的小鼠模型。本文提出的项目将通过使用在Pten基因中具有特定病变的基因工程小鼠，在细胞和分子水平上研究饮食在PCa中的作用。（i）确定高脂肪饮食、生酮饮食和饮食成分或热量摄入对PCa发育的影响;（ii）检验高胆固醇血症促进PCa进展并且其与低密度脂蛋白（LDL）受体的功能失调反馈调节相关的假设，并评估胆固醇和类异戊二烯的内源性产生对癌症进展的影响;（iii）测试过量膳食支链氨基酸对PCa进展的影响和mTORCI信号传导在该应答中的作用，并确定热量限制对PCa的影响是否被雷帕霉素和二甲双胍重演;（iv）通过采用已建立的PCa化疗和化学预防方案，确定PCa中PML对AMPK通路的调节机制以及PCa中PML-AMPK通路的治疗意义。这项及时的癌症生物学研究将由NCI-MMHCC和NIDDK-MMPC的现任成员指导。 相关性：在一生中，美国六分之一的男性将被诊断患有前列腺癌。多种因素导致前列腺癌的高发病率和患病率。其中，肥胖是一个越来越重要的风险因素。该项目将研究饮食在前列腺癌进展中的作用，并作为基于现有小鼠模型设计新治疗方法的途径。