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

基本信息

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
项目类别：
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

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

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项目摘要

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最常见的恶性肿瘤，仅次于肺癌作为癌症相关死亡的原因。大量流行病学数据表明，富含脂肪，牛肉和乳制品的饮食（西方饮食的主要成分）与前列腺癌的风险增加有关。尽管存在这种长期以来的相关性，但尚未确定饮食与癌症之间这种关联的机理解释。有趣的是，最近已经确定，1-甲基酰基 - COA REAMEMASE（AMACR）在超过90％的前列腺癌中过表达，因此现在已成为前列腺癌诊断的标准生物标志物。 AMACR是一种将无法使用的饮食链链脂肪酸转换为可代谢形式的酶。在我们的初步研究中，我们生成了数据，表明AMACR是雄激素调节的，并通过赋予细胞利用这些分支链脂肪酸的能力来促进细胞生长和存活。该提案的主要目的是确定雄激素信号传导之间的联系，对于前列腺生理学和病理学都很重要，以及在前列腺肿瘤发生中摄入西方饮食的分支链脂肪酸，这是西方饮食的主要组成部分。在这里，体外和体内测定的组合将用于1）确定雄激素和分支链脂肪酸调节前列腺细胞生长和生存的机制，以及2）评估富含分支链脂肪酸富含脂肪酸的富含脂肪酸对前列腺癌的影响。在后一个目的中，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分支链脂肪酸对癌症启动的影响的理解，并为此连接提供早期的机械解释。我们的发现将有对高危患者的饮食建议的直接影响。我们预计，AMACR水平升高的患者将最有可能受益于一种“设计师饮食”方法，该方法可以使用非侵入性和安全的方法来实现潜在的癌细胞。因此，总体而言，该项目的结果将为实施精致的抗癌饮食提供合理的理由。最后，该提案将有助于我们对环境如何与潜在的致癌信号传导过程共同发挥作用以促进前列腺癌。