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: 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
• 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

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.

项目总结/文摘