NAD+ metabolism in prostate cancer

前列腺癌中的 NAD 代谢

• 批准号: 9036948
• 负责人: STEVEN J. KRIDEL
• 金额: $ 30.98万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036948
• 关键词: Affect; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical Trials; Cyclic ADP-Ribose; Data; Development; Enzymes; Epigenetic Process; Epithelial Cells; Equilibrium; Goals; Growth; Human; In Vitro; Investigation; Knowledge; Lead; Link; Lipids; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Mus; Nature; Niacinamide; Nicotinamide adenine dinucleotide; Normal Cell; PTEN gene; Pathway interactions; Phenotype; Positioning Attribute; Process; Prostate; Prostatic Neoplasms; Protein Acetylation; Reaction; Research; Role; Sirtuins; Stem cells; Therapeutic; Tissue Recombination; Transferase; Trefoil; Work; Xenograft procedure; clinically relevant; cofactor; defined contribution; in vivo; inhibitor/antagonist; innovation; insight; lipid biosynthesis; lipid metabolism; macromolecule; metabolic phenotype; neoplastic cell; novel; novel therapeutic intervention; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate carcinogenesis; research study; response; small molecule; tumor; tumor growth; tumor metabolism; tumor progression

DESCRIPTION (provided by applicant): NAD+-dependent pathways have been linked to the control of cellular metabolism, including some pathways involved in lipid metabolism. Prostate cancer is characterized by a lipogenic phenotype. We hypothesize that proper NAD+ metabolism is required to support the lipid-dependent nature of prostate cancer. Specifically, we posit that a trefoil of NAD+-dependent enzymes, namely Nampt, CD38 and the sirtuins control lipid metabolism to support prostate cancer cell survival, wherein the sirtuins act as the metabolic rheostat in response to changes in NAD+ levels. The goal of the proposed work is to understand how NAD+ metabolism establishes epigenetic control of lipid metabolism and prostate tumor growth. By deciphering these mechanisms, this proposal will create new insight into the process required to support tumor cell metabolism and survival. The specific aims of this proposal are 1) To determine how the Nampt-NAD+ axis regulates the epigenetic control of metabolism and survival in prostate cancer, 2) To define how the CD38-NAD+ axis controls metabolism and survival in prostate cancer, and 3) To determine the role of CD38 in the progression of prostate cancer. The results from this study will A) demonstrate how NAD+ metabolism regulates the epigenetic control of lipid metabolism; B) determine whether CD38, the main NAD'ase in cells, acts to suppress prostate cancer, and C) demonstrate how Nampt, CD38 and the sirtuins form a regulatory network to regulate prostate tumor growth. The clinical relevance of the proposal is timely. Lipid metabolism is a recognized target in many cancers, including prostate. Moreover, several small molecule Nampt inhibitors have been developed recently and are being evaluated in clinical trials. In addition, several sirtuin activators and inhibitors have been described. Therefore, it is possible that compounds with the ability to affect NAD+ metabolism and ultimately lipid metabolism will enter the clinic. Altogether, the proposed studies will define the contribution of NAD+ metabolism to prostate cancer and identify methods to reprogram tumor cell metabolism through modulation of NAD+-linked pathways.

描述（由申请方提供）：NAD+依赖性途径与细胞代谢的控制相关，包括参与脂质代谢的一些途径。前列腺癌的特征在于脂肪生成表型。我们假设，需要适当的NAD+代谢来支持前列腺癌的脂质依赖性。具体而言，我们证实，三叶NAD+依赖性酶，即Nampt，CD 38和sirtuins控制脂质代谢，以支持前列腺癌细胞存活，其中sirtuins作为代谢变阻器响应NAD+水平的变化。拟议工作的目标是了解NAD+代谢如何建立脂质代谢和前列腺肿瘤生长的表观遗传控制。通过破译这些机制，该提案将为支持肿瘤细胞代谢和存活所需的过程提供新的见解。该提案的具体目的是1）确定Nampt-NAD+轴如何调节前列腺癌中代谢和存活的表观遗传控制，2）定义CD 38-NAD+轴如何控制前列腺癌中的代谢和存活，以及3）确定CD 38在前列腺癌进展中的作用。本研究的结果将A）证明NAD+代谢如何调节脂质代谢的表观遗传控制; B）确定细胞中的主要NAD'酶CD 38是否起到抑制前列腺癌的作用，以及C）证明Nampt、CD 38和sirtuins如何形成调节前列腺肿瘤生长的调节网络。该提案的临床相关性是及时的。脂质代谢是许多癌症（包括前列腺癌）的公认靶点。此外，最近已经开发了几种小分子Nampt抑制剂，并正在临床试验中进行评估。此外，已经描述了几种去乙酰化酶激活剂和抑制剂。因此，有可能具有影响能力的化合物 NAD+代谢和最终脂质代谢将进入临床。总之，拟议的研究将确定NAD+代谢对前列腺癌的贡献，并确定通过调节NAD+相关途径重新编程肿瘤细胞代谢的方法。