Targeting Acetyl-CoA Metabolism for the Discovery of New Anti-Cancer Therapeutics

描述（由申请人提供）：细胞的生长和增殖如何与代谢和细胞的代谢状态协调是一个重要的未解决的问题，这对于理解导致癌症的代谢改变至关重要。癌细胞经常表现出高度的糖酵解代谢，消耗大量的葡萄糖来促进增殖。然而，细胞将葡萄糖和碳源可用性作为增殖能力的衡量标准的机制仍然存在争议，而且人们对其知之甚少。尽管人们对癌症代谢重新产生了兴趣，但尚不清楚细胞代谢的哪个方面可能代表肿瘤而不是正常细胞的现实的、可靶向的易感性。我们最近发现乙酰辅酶a代表了碳源的关键代谢物，作为生长的关键代谢信号。在进入生长阶段后，细胞上调乙酰辅酶a的产生，从而诱导组蛋白乙酰化，特别是在那些对生长重要的基因上。因此，乙酰辅酶a促进这些生长基因的表达，从而促进增殖。初步数据表明，哺乳动物细胞中也存在类似的代谢生长控制机制。这些和其他考虑导致认识到特定的酶和蛋白质可能在促进乙酰辅酶a诱导的生长反应途径中发挥关键作用。本提案的目标是全面研究针对乙酰辅酶a代谢方面的可行性，以发现抗癌治疗方法。

DESCRIPTION (provided by applicant): How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell is an important unresolved question that is critical to understanding the metabolic alterations that contribute to cancer. Cancer cells frequently exhibit a highly glycolytic metabolism and consume substantial quantities of glucose to promote proliferation. However, the mechanisms by which glucose and carbon source availability are sensed by a cell as a measure of proliferative capacity remain controversial and poorly understood. Despite renewed interest in cancer metabolism, it has been unclear which aspect of cellular metabolism might represent a realistic, targetable vulnerability of tumors but not normal cells. We recently discovered that acetyl-CoA represents the key metabolite of carbon sources that functions as a critical metabolic signal for growth. Upon entry into growth, cells upregulate the production of acetyl- CoA which consequently induces the acetylation of histones specifically at those genes important for growth. As such, acetyl-CoA enables the expression of these growth genes and thus commitment to proliferation. Preliminary data suggest that a similar metabolic growth control mechanism exists in mammalian cells. These and other considerations have led to the realization that particular enzymes and proteins may play critical roles in fueling the acetyl-CoA- induced growth response pathway. The goal of this proposal is to comprehensively investigate the feasibility of targeting aspects of acetyl-CoA metabolism for the discovery of anti-cancer therapeutics.