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.

项目摘要/摘要 人们对致癌驱动基因突变和肿瘤抑制基因缺失的影响重新产生了兴趣。 细胞代谢中与癌症相关的变化。大部分的努力都集中在与 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，这一过程 这被称为有氧糖酵解或“沃堡效应”。这种看似浪费的新陈代谢一直困扰着癌症。 几十年来一直是生物学家。然而，有氧糖酵解已被证明是一种可持续的方式来支持 糖酵解中间体的连续生产，用于蛋白质、脂类、 和核酸。十多年前，汤普森实验室开始分析肿瘤对 谷氨酰胺，细胞外液中第二种最常见的营养物质。而葡萄糖的代谢是通过 癌细胞主要在胞浆中，我们发现谷氨酰胺主要在线粒体中代谢。 与葡萄糖类似，我们发现被吸收为谷氨酰胺的大部分碳以乳酸的形式分泌，a 这个过程现在被称为谷氨酰胺分解。从那时起，谷氨酰胺分解作用的研究就集中在 谷氨酰胺作为逆性底物，当碳从TCA中去除时，维持线粒体的功能 以柠檬酸的形式循环，以促进脂肪酸的生物合成，并作为天冬氨酸来支持核苷酸的生物合成。 肿瘤细胞体内对谷氨酰胺的亲和力和谷氨酰胺分解代谢维持氧化的能力 通过TCA循环逆转的磷酸化已在体内得到证实。然而，它的作用是 谷氨酰胺分解在支持肿瘤氮代谢中的作用还不是很清楚。尽管抑制药物的作用 谷氨酰胺代谢在癌症治疗中已经被探索过，他们在临床上的成功在一定程度上是有限的 因为我们对肿瘤氮代谢的了解不完全。了解氮的作用 新陈代谢在支持癌细胞生存和生长方面已经成为Thompson研究的中心焦点 实验室。我们目前正在探索一种假设，即依赖谷氨酰胺的线粒体谷氨酸 堆积为细胞提供了一种细胞内还原的氮储备，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的生成。 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是由 细胞外谷氨酰胺摄取，我们还计划测试乳酸和氨的结合是否 在营养贫乏的条件下在肿瘤微环境(TME)中积累的可以用来修复 线粒体谷氨酸和胞浆谷氨酰胺达到支持适应性翻译和细胞生存的水平。 这些结果将有助于阐明癌细胞对氮的亲和力是如何基于营养可获得性和 特定致癌基因突变和肿瘤抑制基因缺失的存在。所获得的见解将有助于 为癌症的诊断和治疗塑造新的方法。