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

项目总结/摘要 葡萄糖是癌细胞增殖的必需燃料，既作为ATP产生的底物， 作为生物质积累不可替代的碳源。癌细胞对葡萄糖特别上瘾 但只是将大部分以乳酸盐的形式分泌（称为有氧糖酵解或瓦尔堡效应），从而产生 不适宜的葡萄糖贫乏和乳酸盐丰富的微环境，否则对大多数细胞是致命的。 然而，癌细胞可以有效地利用有限的葡萄糖和过量的乳酸盐进行无限生长， 机制不明。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循环超过葡萄糖，以增加氧化磷酸化（OXPHOS）活性，这反过来又抑制 糖酵解以保存细胞外葡萄糖，这表明癌细胞依赖于乳酸盐诱导的OXPHOS 最佳增长。拟议的研究旨在从机制上剖析代谢之间的相互作用， 乳酸盐介导的线粒体OXPHOS和糖酵解（目的1和3），并评估 靶向癌症中的乳酸氧化（Aim 2）。具体目标如下：目标1。确定 乳酸盐介导OXPHOS增加如何抑制糖酵解;目的2.评估体内治疗 潜在的靶向乳酸氧化使用Phenestrin;目的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 通过这些学习获得的专业知识将有助于我向独立过渡，我的长期目标是 作为一名医生科学家，研究并瞄准癌症中的代谢弱点。 除了科学的目标，我还在这份申请中概述了详细的职业发展计划， 获得领导独立研究实验室所需的技能。拟议的研究和 培训计划将在克雷格汤普森博士的指导下进行。Memorial Sloan-Kettering 癌症中心，沿着与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，以实现这些目标为我过渡到独立。

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.