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

基本信息

批准号：
10745359
负责人：
Xin Cai
金额：
$ 24.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745359
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 Permeability Phenformin Phosphorylation Inhibition Physicians Postdoctoral Fellow Production Proliferating Proteins Pyruvate Regulation Reporter Research Scientist Serum Source Therapeutic Training Universities Warburg Effect aerobic glycolysis cancer cell cancer therapy career development clinical training design extracellular imaging modality in vivo inhibitor insight liquid chromatography mass spectrometry medical schools metabolomics novel oxidation patient derived xenograft model research and development response skills tumor tumor metabolism tumor microenvironment

项目摘要

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。