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 人们对致癌驱动突变和抑制肿瘤损失的贡献有了新的兴趣 与癌症相关的细胞代谢改变。大部分努力都集中在流行中 大多数癌细胞仅摄入葡萄糖才能释放大多数葡萄糖碳，这是一个过程 被称为有氧糖酵解或“沃伯格效应”。这似乎浪费的新陈代谢困扰着癌症 生物学家数十年。然而，有氧糖酵解已被证明是一种可持续的支持方式 在从头合成蛋白质，脂质，脂质，脂质中的糖酵解中间体的连续产生 和核酸。十年前，汤普森实验室开始进行分析的肿瘤利用 谷氨酰胺，是细胞外液中第二常见的营养剂。而葡萄糖被代谢 癌细胞主要在细胞质中，我们发现谷氨酰胺在线粒体中被代谢。 与葡萄糖类似，我们发现大多数碳含有谷氨酰胺为牙胶，一个 现在称为谷氨酰胺溶解的过程。自那时以来，谷氨酰胺溶解的研究集中在 谷氨酰胺作为一种无粘膜底物，以维持线粒体功能，因为从TCA中取出碳 以柠檬酸盐的形式循环燃料脂肪酸生物合成和天冬氨酸以支持核苷酸生物合成。 谷氨酰胺在体内的肿瘤细胞流行和谷氨酰胺分解代谢保持氧化的能力 通过TCA循环流浪性通过体内证实了通过TCA循环流浪性的磷酸化。但是， 支持肿瘤氮代谢方面的谷氨酰胺溶解知之甚少。虽然抑制剂 谷氨酰胺代谢已在癌症疗法中探讨，它们在诊所的成功部分受到限制 因为我们对肿瘤氮代谢的了解不完全。了解氮的作用 支持癌细胞存活和生长的代谢已成为汤普森的核心重点 实验室。我们目前正在探讨谷氨酰胺依赖性线粒体谷氨酸的假设 积累为细胞提供了减少氮的细胞内储备，可以针对 从头多胺产生，氨基酸生物合成和谷胱甘肽产生的线粒体支持。 我们还研究线粒体谷氨酸的差异命运如何受到生长因子的调节，因为 以及通过癌基因和肿瘤补充剂。线粒体谷氨酸的正常池被喂食 细胞外谷氨酰胺摄取，我们还计划测试鞋类和氨的组合 可以利用在营养贫困条件下积聚在肿瘤微环境（TME）中 线粒体谷氨酸和胞质谷氨酰胺至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基于营养的可用性和 特定的致癌突变和肿瘤抑制损失的存在。获得的见解将有助于 塑造用于诊断和治疗癌症的新方法。