Defining an acetyl-CoA sensing mechanism as a form of inter-organelle communication in cancer

将乙酰辅酶A传感机制定义为癌症细胞器间通讯的一种形式

• 批准号: 10164732
• 负责人: Kathryn Elaine Wellen
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164732
• 关键词: 5' -AMP-activated protein kinase; ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acetylation; Address; Anabolism; Applications Grants; Binding Proteins; Bioenergetics; Catabolism; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Cholesterol; Citrates; Clinical Trials; Coenzyme A Ligases; Communication; Consumption; Cytosol; Data; Dependence; Endoplasmic Reticulum; Ensure; Enzymes; Family member; Gene Expression Regulation; Generations; Genetic; Glucose; Glutamine; Goals; Grant; Histone Acetylation; Histone Deacetylation; Hypoxia; Impairment; Kinetics; Lipids; Liver; Location; Lysine; Malignant Neoplasms; Mediating; Membrane; Metabolic; Metabolism; Mitochondria; Monitor; Nuclear; Nutrient; Organelles; Oxygen; Pathway interactions; Phenotype; Positioning Attribute; Process; Production; Protein Isoforms; Protein Precursors; Proteomics; Publishing; Reagent; Recycling; Regulatory Element; Reporting; Serum; Signal Transduction; Sterols; Supporting Cell; Testing; Therapeutic; Time; Up-Regulation; Withdrawal; Work; cancer cell; cancer therapy; deprivation; detection of nutrient; falls; flexibility; improved; metabolomics; neoplastic cell; prevent; response; therapeutic target; therapeutically effective; therapy resistant; transcription factor; tumor; tumor metabolism

PROJECT SUMMARY Cancer cells are subjected to variable and often severely nutrient-limited microenvironments to which they must adapt in order to survive. In addition, effective therapeutic targeting of cancer metabolism requires an understanding of the compensatory networks and mechanisms of metabolic flexibility that are engaged when a metabolic enzyme is inhibited. In order for cells to activate compensatory mechanisms, they must first be able to detect a metabolic deficiency. This is exemplified by AMP-activated protein kinase (AMPK), which senses a rise in the AMP/ATP ratio and mediates signaling effects to reduce ATP consumption and enhance ATP production. Abundant evidence now indicates that acetyl-CoA is also a key metabolite that is closely monitored by cells and that adaptive mechanisms are engaged when its availability is limited. Moreover, ongoing clinical trials indicate that a therapeutic window exists for targeting the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY), at least in the liver. We previously reported that in response to ACLY inhibition or Acly genetic deletion, the enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2), which generates acetyl-CoA from acetate, is upregulated and supports cell viability and proliferation. Moreover, acetate, which is normally dispensable for cells, becomes essential for survival in the absence of ACLY. However, the mechanisms through which cells sense a deficiency in acetyl-CoA and implement this adaptive response remain unknown. In this grant application, building on published and preliminary data and leveraging reagents generated in our lab and the metabolomics and proteomics expertise of our long-time collaborators, we propose an approach to address the fundamental question of how cells sense acetyl-CoA. We hypothesize that acetyl-CoA sensing requires close intraorganelle communication between the mitochondria, cytosol, endoplasmic reticulum, and nucleus. We will: 1) determine the subcellular location at which acetyl-CoA production is sensed to promote ACSS2 upregulation; 2) define the mechanisms through which acetyl-CoA insufficiency is sensed to induce ACSS2 upregulation; and 3) identify the functions of nuclear-cytosolic acetyl-CoA that are essential for viability. Findings from this study will both define fundamental mechanisms of nutrient sensing and inform optimal approaches for targeting acetyl-CoA metabolism therapeutically.

项目摘要 癌细胞受到可变且经常严重的营养限制的微环境的影响。 必须适应才能生存。此外，有效的癌症代谢靶向靶向 了解当涉及代谢网络和代谢灵活性机制 抑制代谢酶。为了激活补偿机制，它们必须首先能够 检测代谢缺陷。这是通过AMP激活的蛋白激酶（AMPK）来体现的，该蛋白激酶（AMPK）感觉到 AMP/ATP比率上升并介导信号传导效应以减少ATP消耗并增强ATP 生产。现在，大量证据表明乙酰辅酶A也是密钥代谢物 通过细胞监测，自适应机制在限制时会参与。而且， 正在进行的临床试验表明，存在用于靶向乙酰辅酶A的治疗窗口 至少在肝脏中，ATP-CITRATE裂解酶（ACLY）。我们以前报道说，应响应Acly抑制或 Acly遗传缺失，酶酰基-COA合成酶短链家族成员2（ACSS2），其中 从乙酸酯产生乙酰辅酶A，被上调并支持细胞活力和增殖。而且， 通常对于细胞的乙酸酯，对于在没有Acly的情况下来说，对于存活而言至关重要。 但是，细胞感知乙酰辅酶A缺乏并实现这种适应性的机制 响应仍然未知。 在此赠款应用程序中，基于已发布和初步的数据以及我们在我们的 实验室以及我们长期合作者的代谢组学和蛋白质组学专业知识，我们提出了一种方法 解决细胞如何感知乙酰辅酶A的基本问题。我们假设乙酰辅酶A传感 需要在线粒体，细胞质，内质网和 核。我们将：1）确定感测乙酰辅酶A的亚细胞位置以促进 ACSS2上调； 2）定义乙酰辅酶A的机制感测到诱导的机制 ACSS2上调； 3）确定对生存能力必不可少的核溶质膜乙酰辅酶A的功能。 这项研究的结果既将定义营养感应的基本机制，又将为最佳提供信息 治疗靶向乙酰辅酶A代谢的方法。