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: 10402827
• 负责人: Kathryn Elaine Wellen
• 金额: $ 36.39万
• 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/10402827
• 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.

项目概要 癌细胞所处的微环境变化多端，而且往往营养严重有限。 必须适应才能生存。此外，针对癌症代谢的有效治疗目标需要 了解代谢灵活性的补偿网络和机制 代谢酶受到抑制。为了让细胞激活补偿机制，它们首先必须能够 来检测代谢缺陷。 AMP 激活蛋白激酶 (AMPK) 就是一个例子，它可以感知 AMP/ATP 比率上升并介导信号传导效应，从而减少 ATP 消耗并增强 ATP 生产。现在大量的证据表明乙酰辅酶A也是一种密切相关的关键代谢物。 由细胞监控，当其可用性有限时，自适应机制就会启动。而且， 正在进行的临床试验表明存在针对乙酰辅酶A产生酶的治疗窗口 ATP-柠檬酸裂解酶（ACLY），至少在肝脏中。我们之前报道过，为了响应 ACLY 抑制或 Acly 基因缺失，即酰基辅酶 A 合成酶短链家族成员 2 (ACSS2)， 从乙酸盐中生成乙酰辅酶A，上调并支持细胞活力和增殖。而且， 醋酸盐通常对细胞来说是可有可无的，但在缺乏 ACLY 的情况下却对细胞的生存至关重要。 然而，细胞感知乙酰辅酶A缺乏并实施这种适应性的机制 回应仍未知。 在此拨款申请中，以已发布的初步数据为基础，并利用我们生成的试剂 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 需要线粒体、细胞质、内质网和细胞器之间密切的细胞器内通讯 核。我们将：1) 确定乙酰辅酶 A 产生被感知以促进的亚细胞位置 ACSS2 上调； 2) 定义乙酰辅酶A不足的感知机制 ACSS2 上调； 3) 确定核胞质乙酰辅酶A对于生存至关重要的功能。 这项研究的结果将定义营养传感的基本机制，并为最佳选择提供信息。 靶向乙酰辅酶A代谢的治疗方法。

项目成果

Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.

• DOI: 10.1126/sciadv.adf0115
• 发表时间: 2023-05-03
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Izzo, Luke T.;Trefely, Sophie;Demetriadou, Christina;Drummond, Jack M.;Mizukami, Takuya;Kuprasertkul, Nina;Farria, Aimee T.;Nguyen, Phuong T. T.;Murali, Nivitha;Reich, Lauren;Kantner, Daniel S.;Shaffer, Joshua;Affronti, Hayley;Carrer, Alessandro;Andrews, Andrew;Capell, Brian C.;Snyder, Nathaniel W.;Wellen, Kathryn E.
• 通讯作者: Wellen, Kathryn E.