Exploring the Role of Nitrogen Metabolism in Cancer

探索氮代谢在癌症中的作用

• 批准号: 10737792
• 负责人: CRAIG B THOMPSON
• 金额: $ 92.63万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2030-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737792
• 关键词: Amino Acids; Ammonia; Anabolism; Aspartate; Avidity; Cancer Cell Growth; Carbon; Catabolism; Cell Survival; Cells; Citrates; Citric Acid Cycle; Clinic; Cytosol; Diagnosis; Extracellular Fluid; Generations; Glucose; Glutamates; Glutamine; Glutathione; Growth Factor; Knowledge; Laboratories; Lipids; Malignant Neoplasms; Metabolism; Mitochondria; Mutation; Nitrogen; Nucleic Acids; Nucleotide Biosynthesis; Nutrient; Nutrient availability; Oncogenes; Oncogenic; Oxidative Phosphorylation; Play; Polyamines; Process; Production; Protein Biosynthesis; Regulation; Role; Shapes; Testing; Time; Translations; Tumor Suppressor Proteins; Warburg Effect; aerobic glycolysis; aminoacid biosynthesis; cancer cell; cancer therapy; cell growth; driver mutation; extracellular; fatty acid biosynthesis; in vivo; inhibitor; insight; interest; neoplastic cell; nitrogen metabolism; novel diagnostics; novel strategies; novel therapeutic intervention; success; tumor; tumor metabolism; tumor microenvironment; uptake

PROJECT SUMMARY/ABSTRACT There has been a renewed interest in how oncogenic driver mutations and tumor suppressor losses contribute to cancer-associated alterations in cellular metabolism. Much of the effort has been focused on the avidity with which most cancer cells take up glucose only to release most of the glucose carbon as lactate, a process known as aerobic glycolysis or the “Warburg Effect”. This seemingly wasteful metabolism has puzzled cancer biologists for decades. Nevertheless, aerobic glycolysis has been shown to be a sustainable way to support the continuous production of glycolytic intermediates that are utilized in de novo synthesis of proteins, lipids, and nucleic acids. Over a decade ago, the Thompson laboratory embarked on analyzing tumor utilization of glutamine, the second most common nutrient present in extracellular fluid. While glucose is metabolized by cancer cells primarily in the cytosol, we found that glutamine was metabolized primarily in the mitochondria. Similar to glucose, we found that the majority of the carbon taken up as glutamine was secreted as lactate, a process now known as glutaminolysis. Since that time, the study of glutaminolysis has focused on the role of glutamine as an anaplerotic substrate to maintain mitochondrial function as carbon is taken out of the TCA cycle in the form of citrate to fuel fatty acid biosynthesis and as aspartate to support nucleotide biosynthesis. Tumor cell avidity for glutamine in vivo and the ability of glutamine catabolism to maintain oxidative phosphorylation through TCA cycle anaplerosis has been confirmed in vivo. However, the role of glutaminolysis in supporting tumor nitrogen metabolism is less well understood. Although inhibitors of glutamine metabolism have been explored in cancer therapy, their success in the clinic has been limited in part because of our incomplete knowledge of tumor nitrogen metabolism. Understanding the role of nitrogen metabolism in supporting cancer cell survival and growth has become the central focus of the Thompson laboratory. We are currently exploring the hypothesis that glutamine-dependent mitochondrial glutamate accumulation provides the cell with an intracellular reserve of reduced nitrogen that can be directed toward mitochondrial support of de novo polyamine production, amino acid biosynthesis, and glutathione generation. We are also studying how the differential fates of mitochondrial glutamate are regulated by growth factors, as well as by oncogenes and tumor suppressors. While the normal pool of mitochondrial glutamate is fed by extracellular glutamine uptake, we also plan to test whether the combination of lactate and ammonia that accumulates in the tumor microenvironment (TME) under nutrient-poor conditions can be utilized to restore mitochondrial glutamate and cytosolic glutamine to levels that support adaptive translation and cell survival. These results will help clarify how cancer cell avidity for nitrogen is satisfied based on nutrient availability and the presence of specific oncogenic mutations and tumor suppressor losses. The insights gained will help to shape new approaches for the diagnosis and treatment of cancer.

项目概要/摘要 人们对致癌驱动突变和抑癌基因缺失如何产生新的兴趣 大部分努力都集中在与癌症相关的细胞代谢改变上。 大多数癌细胞只吸收葡萄糖，然后以乳酸的形式释放大部分葡萄糖碳，这是一个过程 这种看似浪费的新陈代谢一直困扰着癌症。 然而，几十年来，有氧糖酵解已被证明是一种可持续的支持方式。 连续生产糖酵解中间体，用于从头合成蛋白质、脂质、 十多年前，汤普森实验室开始分析肿瘤的利用。 谷氨酰胺是细胞外液中第二常见的营养物质，而葡萄糖则被代谢。 癌细胞主要在细胞质中，我们发现谷氨酰胺主要在线粒体中代谢。 与葡萄糖类似，我们发现大部分以谷氨酰胺形式吸收的碳都以乳酸的形式分泌，乳酸是一种 现在称为谷氨酰胺分解的过程从那时起，谷氨酰胺分解的研究就集中在谷氨酰胺分解的作用上。 当碳从 TCA 中取出时，谷氨酰胺作为回补底物以维持线粒体功能 以柠檬酸形式循环以促进脂肪酸生物合成，以天冬氨酸形式循环以支持核苷酸生物合成。 体内肿瘤细胞对谷氨酰胺的亲和力以及谷氨酰胺分解代谢维持氧化的能力 磷酸化通过TCA循环回补的作用已在体内得到证实。 尽管谷氨酰胺分解的抑制剂对于支持肿瘤氮代谢的作用还不太了解。 谷氨酰胺代谢已在癌症治疗中进行了探索，但其在临床上的成功部分受到限制 因为我们对肿瘤氮代谢的了解还不完全。 支持癌细胞存活和生长的代谢已成为 Thompson 的中心焦点 我们实验室目前正在探索谷氨酰胺依赖性线粒体谷氨酸的假设。 积累为细胞提供了细胞内减少的氮储备，可以直接用于 线粒体支持从头产生多胺、氨基酸生物合成和谷胱甘肽生成。 我们还在研究生长因子如何调节线粒体谷氨酸的不同命运，如 以及癌基因和肿瘤抑制因子，而正常的线粒体谷氨酸池则由癌基因和肿瘤抑制因子提供。 细胞外谷氨酰胺的摄取，我们还计划测试乳酸和氨的组合是否 在营养不良的条件下在肿瘤微环境（TME）中积累，可用于恢复 线粒体谷氨酸和胞质谷氨酰胺达到支持适应性翻译和细胞存活的水平。 这些结果将有助于阐明癌细胞对氮的亲和力是如何根据营养可用性和 特定致癌突变的存在和肿瘤抑制因子的丧失将有助于 制定癌症诊断和治疗的新方法。