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

靶向乙酰辅酶A代谢以发现新的抗癌疗法

• 批准号: 8674809
• 负责人: STEVEN L MCKNIGHT
• 金额: $ 47.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8674809
• 关键词: Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Antibodies; Biochemical; Bioinformatics; Biological Assay; Cancer Center; Carbon; Cell Cycle; Cell Proliferation; Cells; Collaborations; Complex; Data; Dependence; Engineering; Enzymes; Epithelial; Exhibits; Fatty Acids; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Glucose; Goals; Growth; Hepatocyte; Histone Acetylation; Human; Hypoxia; Investigation; Knock-out; Lead; Liver; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mammalian Cell; Measures; Metabolic; Metabolism; MicroRNAs; Modeling; Mus; Non-Small-Cell Lung Carcinoma; Normal Cell; Nuclear; PTEN gene; Pathway interactions; Phase; Play; Positron-Emission Tomography; Predictive Value; Primary carcinoma of the liver cells; Process; Production; Protein Array; Proteins; Proteome; Pyruvate; Resources; Roentgen Rays; Role; SV40 T Antigens; Signal Transduction; Source; Sterols; Structure; Testing; Therapeutic; Tumor Burden; anti-cancer therapeutic; c-myc Genes; cancer cell; cancer therapy; cell growth; comparative genomic hybridization; improved; inhibitor/antagonist; insight; interest; mRNA Expression; malignant breast neoplasm; mouse model; novel; overexpression; prognostic; public health relevance; response; small molecule; tool; tumor; tumor growth; tumor initiation; tumor metabolism; tumorigenesis

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.

描述（由申请人提供）：细胞生长和增殖如何与细胞的代谢和代谢状态协调是一个重要的未解决问题，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糖酵解代谢，并消耗大量葡萄糖来促进增殖。然而，葡萄糖和碳源的可用性被细胞感知作为增殖能力的量度的机制仍然存在争议并且知之甚少。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、可靶向的脆弱性。我们最近发现，乙酰辅酶A代表碳源的关键代谢产物，作为生长的关键代谢信号。在进入生长期后，细胞上调乙酰辅酶A的产生，从而特异性地在那些对生长重要的基因处诱导组蛋白的乙酰化。因此，乙酰辅酶A使这些生长基因的表达，从而致力于增殖。初步数据表明，在哺乳动物细胞中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。该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，以发现抗癌疗法。