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

基本信息

批准号：
9021622
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
项目类别：
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/9021622
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 Chips Gene Expression Genes Genetic Genome Glucose Goals Growth Health 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 genetic approach improved inhibitor/antagonist insight interest mRNA Expression malignant breast neoplasm mouse model novel overexpression prognostic value response small molecule small molecule inhibitor tool transcriptome tumor tumor growth tumor initiation tumor metabolism tumorigenesis

项目摘要

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）：细胞的生长和增殖如何与代谢协调和细胞的代谢状态是一个重要的未解决的问题，这对于理解有助于癌症的代谢改变至关重要。癌细胞经常表现出高度糖酵解的代谢，并消耗大量葡萄糖以促进增殖。然而，通过细胞感知葡萄糖和碳源可用性的机制作为增生能力的量度仍然有争议且理解不足。尽管对癌症代谢产生了重新兴趣，但尚不清楚细胞代谢的哪个方面可能代表肿瘤的现实，可靶向的脆弱性，而不是正常细胞。我们最近发现，乙酰-COA代表了碳源的关键代谢产物，该代谢物是生长的关键代谢信号。进入生长后，细胞上调了乙酰基CoA的产生，从而诱导组蛋白的乙酰化在对生长至关重要的基因上。因此，乙酰辅酶A能够表达这些生长基因，从而表达对增殖的承诺。初步数据表明，哺乳动物细胞中存在类似的代谢生长控制机制。这些考虑和其他考虑因素已意识到特定的酶和蛋白质可能在加油乙酰氧气诱导的生长反应途径中起关键作用。该提案的目的是全面研究靶向乙酰-COA代谢方面以发现抗癌治疗剂的可行性。