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

描述（由申请人提供）：前列腺癌是美国男性中最常见的恶性肿瘤，是仅次于肺癌的癌症相关死亡原因。大量流行病学数据表明，富含脂肪、牛肉和奶制品（西方饮食的主要组成部分）的饮食与前列腺癌风险增加有关。尽管这种早就为人所知的相关性，饮食和癌症之间联系的机制解释尚未被明确。有趣的是，最近已经确定，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，可以将不可用的膳食支链脂肪酸转化为可代谢的形式。在我们的初步研究中，我们已经获得的数据表明，AMACR是雄激素调节的，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。本提案的主要目标是确定雄激素信号（对前列腺生理和病理都很重要）与摄入支链脂肪酸（西方饮食的主要成分）在前列腺肿瘤发生中的联系。本研究将采用体内和体外实验相结合的方法：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；2)评估富含支链脂肪酸的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对支链脂肪酸对癌症起始的影响的理解，并为这一联系提供早期的机制解释。我们的研究结果

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. PUBLIC HEALTH RELEVANCE: For years it has been known that a diet rich in ruminant fats, beef and dairy products (components of the Western diet) increases a man's risk of developing prostate cancer. Despite this known link, it is not fully understood why these foods put men at risk. This proposal investigates whether a specific aspect of the Western diet, namely branched-chain fatty acids, promotes prostate tumorigenesis. Understanding how certain diets impact cancer risk will maximize disease prevention by facilitating the improvement of dietary recommendations.