Modulation of Branched-Chain Fatty Acids for the Prevention of Prostate Cancer

调节支链脂肪酸预防前列腺癌

• 批准号: 8469411
• 负责人: Daniel Edward Frigo
• 金额: $ 7.05万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-14 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469411
• 关键词: Acetyl Coenzyme A; Acids; Address; American; Androgens; Animals; Bacteria; Bioenergetics; Biological Assay; Biological Markers; Cancer Etiology; Cattle; Cell Proliferation; Cell Survival; Cells; Cessation of life; Coenzyme A; Consensus; Consumption; Dairy Products; Data; Diagnosis; Diet; Disease; Energy-Generating Resources; Environment; Enzymes; Epidemiology; Epithelial Cells; Etiology; Fatty acid glycerol esters; Food; Foundations; Genes; Goals; Goat; Growth; Human; In Vitro; Incidence; Ingestion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metabolism; Modeling; Molecular; Oncogenic; Outcome; Pathology; Pathway interactions; Patients; Physiology; Phytol; Pre-Clinical Model; Prostate; Racemases; Recommendation; Research; Risk; Role; Rumen; Ruminants; SCID Mice; Signal Transduction; Source; Testing; Transgenic Model; Tumor Biology; Ungulate; Xenograft Model; Xenograft procedure; beef; branched chain fatty acid; cancer cell; cancer diagnosis; cancer initiation; cancer risk; cell growth; computerized data processing; diet and cancer; disorder prevention; fatty acid metabolism; fatty acid oxidation; in vitro Assay; in vivo; man; men; mouse model; novel; overexpression; oxidation; prostate cancer prevention; prostate carcinogenesis; research study; tumorigenesis

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed malignancy in American men, and is second only to lung cancer as a cause of cancer-related deaths. Considerable epidemiological data suggest that a diet rich in fats, beef and dairy products (major components of the Western diet) correlates with an increased risk of prostate cancer. Despite this long-known correlation, a mechanistic explanation for this association between diet and cancer has not yet been defined. Interestingly, it has recently been determined that 1-methylacyl- CoA racemase (AMACR) is overexpressed in greater than 90% of prostate cancers and hence, is now a standard biomarker for prostate cancer diagnosis. AMACR is an enzyme that converts unusable dietary branched-chain fatty acids to a metabolizable form. In our preliminary studies, we have generated data indicating that AMACR is androgen-regulated and promotes cell growth and survival by conferring cells the ability to utilize these branched-chain fatty acids. The primary goal of this proposal is to identify the connections between androgen signaling, important for both prostate physiology and pathology, and ingestion of branched-chain fatty acids, a major component of the Western diet, in prostate tumorigenesis. Here, a combination of in vitro and in vivo assays will be used to 1) Determine the mechanism(s) by which androgens and branched-chain fatty acids regulate prostate cell growth and survival and 2) Evaluate the impact of a branched-chain fatty acid-rich diet on prostate cancer in vivo. In this latter aim, we will use both transgenic and xenograft models of prostate cancer to facilitate our understanding of the influence of branched-chain fatty acids on cancer initiation and provide early mechanistic explanations for this link. Our findings will have direct implications for the improvement of dietary recommendations for at-risk patients. We expect that patients with elevated AMACR levels would be the most likely to benefit from a "designer diet" approach that functions to essentially starve potential cancer cells using a non-invasive and safe approach. Hence, collectively the results of this project will provide a rational for the implementation of a refined anticancer diet. Finally, this proposal will contribute to our overall understanding of how the environment functions in concert with potential oncogenic signaling processes to promote prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断出的恶性肿瘤，在癌症相关死亡原因中仅次于肺癌。大量流行病学数据表明，富含脂肪、牛肉和乳制品（西方饮食的主要成分）的饮食与前列腺癌风险增加相关。尽管这种相关性早已为人所知，但饮食与癌症之间这种关联的机制解释尚未确定。有趣的是，最近确定 1-甲基酰基辅酶 A 消旋酶 (AMACR) 在超过 90% 的前列腺癌中过度表达，因此现在是前列腺癌诊断的标准生物标志物。 AMACR 是一种酶，可将无用的膳食支链脂肪酸转化为可代谢形式。在我们的初步研究中，我们生成的数据表明 AMACR 受雄激素调节，并通过赋予细胞利用这些支链脂肪酸的能力来促进细胞生长和存活。该提案的主要目标是确定对前列腺生理学和病理学都很重要的雄激素信号传导与前列腺肿瘤发生中支链脂肪酸（西方饮食的主要组成部分）的摄入之间的联系。 在此，将结合体外和体内测定来 1) 确定雄激素和支链脂肪酸调节前列腺细胞生长和存活的机制，以及 2) 评估支链脂肪的影响富酸饮食对体内前列腺癌的影响。在后一个目标中，我们将使用前列腺癌的转基因和异种移植模型来促进我们了解支链脂肪酸对癌症发生的影响，并为这种联系提供早期机制解释。 我们的研究结果将有 对改善高危患者的饮食建议有直接影响。我们预计，AMACR 水平升高的患者最有可能从“设计饮食”方法中受益，该方法使用非侵入性且安全的方法从根本上饿死潜在的癌细胞。因此，总的来说，该项目的结果将为实施精细抗癌饮食提供合理依据。最后，该提案将有助于我们全面了解环境如何与潜在的致癌信号传导过程协同作用，从而促进前列腺癌。