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

描述（由申请人提供）：前列腺癌（PCa）是男性癌症相关发病和死亡的主要原因之一，仅次于肺癌，约占美国男性癌症死亡总数的10%。前瞻性队列研究显示，肥胖与前列腺癌死亡风险之间存在统计学上显著的正相关。与这些观察结果一致的是，人们注意到热量限制可以防止癌症的发展。最初认为，热量限制对肿瘤进展的影响是细胞生长减少的次要反应；然而，越来越多的人认识到，这一过程实际上影响了关键的细胞内信号通路，特别是胰岛素- igfi和营养介导的PI3K/ mTORCI信号通路，这是大量肿瘤抑制因子所反对的，包括PTEN、TSC1/2、NF1、LKB1、4E-BP1、PDCD4和PML。显然，进一步解决肥胖与前列腺癌相关的分子机制不能仅仅依靠流行病学研究，而需要使用小鼠模型，整合从人类癌症研究中获得的知识。本文提出的项目将在细胞和分子水平上研究饮食在前列腺癌中的作用，方法是使用Pten基因中含有特定病变的基因工程小鼠。该模型将用于以下实验：(i)确定高脂肪饮食、生酮饮食和饮食成分或热量摄入对前列腺癌发展的影响；（ii）检验高胆固醇血症促进前列腺癌进展的假设，以及它与低密度脂蛋白（LDL）受体的功能失调反馈调节有关，并评估内源性胆固醇和类异戊二烯的产生对癌症进展的影响；（iii）测试饮食中过量支链氨基酸对前列腺癌进展的影响，以及mTORCI信号在这一反应中的作用，并确定热量限制对前列腺癌的影响是否可以通过雷帕霉素和二甲双胍重现；（iv）通过采用已建立的PCa化疗和化疗预防方案，确定PML在PCa中调控AMPK通路的机制，以及PML-AMPK通路在PCa中的治疗意义。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。

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.