NAD+ metabolism in prostate cancer

描述(申请人提供)：NAD依赖的途径与细胞新陈代谢的控制有关，包括一些涉及脂类代谢的途径。前列腺癌的特点是产生脂肪的表型。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。具体地说，我们假设NAD依赖酶的三叶结构，即NAMPT、CD38和sirtuins控制脂代谢以支持前列腺癌细胞的生存，其中sirtuins充当代谢变阻器以响应NAD水平的变化。这项拟议工作的目标是了解NAD代谢如何建立对脂肪代谢和前列腺癌生长的表观遗传控制。通过破译这些机制，这项提议将对支持肿瘤细胞新陈代谢和生存所需的过程产生新的见解。这项建议的具体目的是1)确定NAMPT-NAD轴如何调控前列腺癌中代谢和生存的表观遗传控制，2)确定CD38-NAD轴如何控制前列腺癌中的代谢和生存，以及3)确定CD38在前列腺癌进展中的作用。这项研究的结果将A)展示NAD代谢如何调节脂肪代谢的表观遗传控制；B)确定细胞中的主要NAD‘酶CD38是否起到抑制前列腺癌的作用；以及C)展示NAMPT、CD38和sirtuins如何形成调节网络来调节前列腺癌的生长。这项建议的临床意义是及时的。脂代谢是包括前列腺癌在内的许多癌症的公认靶点。此外，最近还开发了几种小分子NAMPT抑制剂，并正在进行临床试验。此外，还描述了几种sirtuin激活剂和抑制剂。因此，有可能具有影响作用的化合物 NAD代谢，最终脂代谢将进入临床。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相关途径来重新编程肿瘤细胞代谢的方法。

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.