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

项目摘要/摘要 葡萄糖是癌细胞增殖的基本燃料，因为它既是产生ATP的底物，也是癌细胞增殖的底物。 作为生物质积累的不可替代的碳源。癌细胞对葡萄糖尤其上瘾。 但只会以乳酸的形式分泌(称为有氧糖酵解或Warburg效应)，从而产生 不适宜居住的葡萄糖贫乏和富含乳酸的微环境，否则对大多数细胞都是致命的。 然而，癌细胞可以有效地利用限制的葡萄糖和过量的乳酸，通过 机制尚不清楚。我的初步数据显示，在低糖条件下，细胞外乳酸 促进癌细胞增殖。从机理上讲，我发现乳酸优先进入线粒体 TCA在葡萄糖上循环以增加氧化磷酸化(OXPHOS)活性，进而抑制 糖酵解保存细胞外葡萄糖，表明癌细胞依赖于乳酸诱导的OXPHOS 最佳增长。拟议的研究旨在机械地剖析代谢的相互作用 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)。正在追求下列具体目标：目标1.确定 乳酸介导的OXPHOS增加如何抑制糖酵解；目的2.评估体内治疗 使用苯福明靶向乳酸氧化的可能性；目标3：从机械上剖析细胞如何区分 优先使用胞外乳酸而不是葡萄糖进入TCA循环。知识与科学 通过这些研究获得的专业知识将促进我向独立的过渡，我的长期目标是 作为一名内科科学家，研究并瞄准癌症中的代谢脆弱性。 除了科学目标，我还在这份申请中概述了详细的职业发展计划，以 掌握领导独立研究实验室所需的技能。拟议的研究和 培训计划将在克雷格·汤普森博士的指导下进行。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 理想的学术环境使我能够实现这些目标，向独立过渡。

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.