Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer

机械剖析乳酸的糖酵解调节及其在癌症中的治疗潜力

• 批准号: 10115324
• 负责人: Xin Cai
• 金额: $ 11.34万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115324
• 关键词: ATP Synthesis Pathway; Acute; Antidiabetic Drugs; Biochemical; Biochemistry; Bioenergetics; Biological Assay; Biomass; Cancer cell line; Carbon; Cell Proliferation; Cells; Chemicals; Citric Acid Cycle; Clinical; Complex; Consumption; Data; Development Plans; Doctor of Philosophy; Electron Transport; Environment; Enzymes; Equilibrium; FDA approved; Genetic; Glucose; Glycolysis; Goals; Growth; Image; In Vitro; Knock-out; Knowledge; Laboratory Research; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Memorial Sloan-Kettering Cancer Center; Mentorship; Metabolic; Metabolism; Methods; Mitochondria; Nutrient; Organelles; Oxidative Phosphorylation; Oxides; Permeability; Phenformin; Physicians; Production; Proteins; Pyruvate; Regulation; Reporter; Research Training; Scientist; Serum; Source; Therapeutic; Training; Universities; Warburg Effect; aerobic glycolysis; cancer cell; cancer therapy; career development; design; extracellular; imaging modality; in vivo; inhibitor/antagonist; insight; liquid chromatography mass spectrometry; medical schools; metabolomics; novel; oxidation; patient derived xenograft model; research and development; response; skills; tumor; tumor metabolism; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Glucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production and as an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucose but only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect), thereby creating an inhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells. However, cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth through unclear mechanisms. My preliminary data revealed that in low glucose conditions, extracellular lactate enhances cancer cell proliferation. Mechanistically, I found that lactate preferentially enters the mitochondria TCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity, which in turn suppresses glycolysis to conserve extracellular glucose, suggesting cancer cells rely on lactate-induced OXPHOS for optimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay between lactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3), and assessing therapeutic potential of targeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determine how lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeutic potential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguish and preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientific expertise gained through these studies will facilitate my transition to independence, with my long-term goal to study and target metabolic vulnerabilities in cancer as a physician scientist. In addition to the scientific goals, I have also outlined a detailed career development plan in this application to obtain skills that are necessary for leading an independent research laboratory. The proposed research and training plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-Kettering Cancer Center, along with the nearby Rockefeller University and Weill Cornell Medical College will provide the ideal academic environment to achieve these goals for me to transition to independence.

项目概要/摘要 葡萄糖是癌细胞增殖的重要燃料，既可以作为 ATP 产生的底物，也可以作为 ATP 生成的底物。 作为生物量积累不可替代的碳源。癌细胞对葡萄糖特别上瘾 但仅以乳酸形式分泌大部分（称为有氧糖酵解或瓦尔堡效应），从而产生 恶劣的缺乏葡萄糖和富含乳酸的微环境，否则对大多数细胞来说是致命的。 然而，癌细胞可以通过以下方式有效地利用有限的葡萄糖和过量的乳酸来无限生长。 机制不明确。我的初步数据显示，在低葡萄糖条件下，细胞外乳酸 增强癌细胞增殖。从机制上讲，我发现乳酸优先进入线粒体 TCA 在葡萄糖上循环，增加氧化磷酸化 (OXPHOS) 活性，从而抑制 糖酵解以保存细胞外葡萄糖，表明癌细胞依赖乳酸诱导的 OXPHOS 最佳增长。拟议的研究旨在机械地剖析之间的代谢相互作用 乳酸介导的线粒体 OXPHOS 和糖酵解（目标 1 和 3），并评估其治疗潜力 针对癌症中的乳酸氧化（目标 2）。正在追求以下具体目标： 目标 1. 确定 乳酸介导的 OXPHOS 增加如何抑制糖酵解；目标 2. 评估体内治疗 使用苯乙双胍靶向乳酸氧化的潜力；目标 3. 机械地剖析细胞如何区分 并优先使用细胞外乳酸而不是葡萄糖进入 TCA 循环。知识和科学 通过这些研究获得的专业知识将有助于我向独立过渡，我的长期目标是 作为一名医学科学家，研究并针对癌症的代谢脆弱性。 除了科学目标之外，我还在这份申请中概述了详细的职业发展计划，以供参考。 获得领导独立研究实验室所需的技能。拟议的研究和 培训计划将在Craig Thompson博士的指导下进行。纪念斯隆-凯特琳 癌症中心以及附近的洛克菲勒大学和威尔康奈尔医学院将提供 实现这些目标的理想学术环境，让我过渡到独立。