Glutamine synthetase in cancer cell metabolism and oncogenesis

谷氨酰胺合成酶在癌细胞代谢和肿瘤发生中的作用

• 批准号: 9981701
• 负责人: Wei-Xing Zong
• 金额: $ 45.14万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981701
• 关键词: Amines; Ammonia; Anabolism; Biochemical Process; Bioenergetics; Biological; Biological Process; Breast; Cancer cell line; Cell Cycle Progression; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Metabolic Process; Citric Acid Cycle; Clinical; Cultured Cells; Data; Development; Dimensions; Disease; Enzymes; Essential Amino Acids; Event; Generations; Genetic Transcription; Glucose; Glutamate Dehydrogenase; Glutamate-Ammonia Ligase; Glutamates; Glutamic Acid; Glutaminase; Glutamine; Growth; Human; Knowledge; Laboratories; Lead; Liver diseases; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mammary gland; Mediating; Metabolic; Metabolism; MicroRNAs; Modeling; Molecular; Mus; Mutation; Non-Essential Amino Acid; Nonesterified Fatty Acids; Nucleotide Biosynthesis; Oncogenes; Oncogenic; Outcome; Pancreas; Pathologic; Patients; Pharmacology; Physical condensation; Play; Process; Production; Proto-Oncogenes; Publications; Reaction; Regulation; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Thymine DNA Glycosylase; Tissues; Tricarboxylic Acids; alpha ketoglutarate; anti-cancer; base; c-myc Genes; cancer cell; cancer type; cell growth; cell type; demethylation; deprivation; design; genetic approach; in vivo; inhibitor/antagonist; malignant breast neoplasm; metabolic abnormality assessment; metabolomics; mouse model; neoplastic; neoplastic cell; nervous system disorder; new therapeutic target; novel; pancreatic cancer model; programs; promoter; public health relevance; stable isotope; success; targeted cancer therapy; therapeutic target; tumor; tumor growth; tumor metabolism; tumor xenograft; tumorigenesis; tumorigenic; uptake

SUMMARY Dysregulated metabolism has long been recognized as a key hallmark of neoplastic disease. One of the major metabolic changes in tumor cells is increased glutamine (Gln) usage via glutaminolysis: Gln is deaminated by glutaminase (GLS) to glutamate (glutamic acid, Glu), which is converted by glutamate dehydrogenase (GLUD) to α-ketoglutarate (aKG) to enter the tricarboxylic acid (TCA) cycle for anaplerosis (replenishment of metabolic intermediates for energy production or biosynthesis). It is well recognized that oncogenic c-Myc (hereafter referred to as Myc) enhances Gln usage by directly transactivating the expression of Gln transporters SLC1A5 and SLC7A5/SLC3A2, and by increasing GLS1 expression via transcriptional suppression of the GLS1 repressor micro RNAs (miR)-23a/b. Pharmacologically targeting GLS1 is being actively pursued as an anti- cancer approach, although thus far with little success. On the other hand, several recent studies, including those from our laboratory, point to the importance of Gln synthesis, at least in certain cell/tissue types. Gln is synthesized de novo by condensation of Glu and ammonia, catalyzed by the enzyme Gln synthetase (GS, also known as glutamate ammonia ligase, GLUL). Using stable isotope-based metabolite tracing, we recently reported that this synthesized Gln is not used via glutaminolysis to fuel the TCA cycle; rather it is used for several TCA-independent anabolic processes including biosynthesis of nucleotides and transport of essential amino acids. Importantly, elevated expression of GS promoted cell survival under Gln limitation; inhibition of GS led to decreased cell proliferation and increased cell death upon Gln limitation, and slowed xenograft tumor growth. Moreover, we recently reported that Myc can induce the expression of GS in a number of cancer cell lines. We also found a positive correlation between Myc activation and GS expression several mouse models and in human patient samples. These findings lead us to propose the following hypothesis: oncogenic Myc, at least in certain cell/tissue types, upregulates GS expression to promote Gln production and its anabolic usage (away from the TCA cycle), thereby facilitating oncogenesis. We propose two Specific Aims to study this hypothesis: 1) Study the metabolic and cell biological consequences, and the regulation of increased GS expression in the context of Myc activation; and 2) Determine the in vivo role of GS in Myc- driven metabolic reprogramming and oncogenesis. If accomplished, this study will provide a novel dimension to understanding the functions of dysregulated Myc in cancer cells and a potential new target for treatment of Myc-driven tumors.

概括 长期以来，代谢失调一直被认为是肿瘤疾病的一个关键标志。主要之一 肿瘤细胞的代谢变化是通过谷氨酰胺分解增加谷氨酰胺 (Gln) 的使用：Gln 通过以下方式脱氨： 谷氨酰胺酶（GLS）转化为谷氨酸（谷氨酸，Glu），由谷氨酸脱氢酶（GLUD）转化 α-酮戊二酸（aKG）进入三羧酸（TCA）循环进行回补（补充代谢 能源生产或生物合成的中间体）。众所周知，致癌性 c-Myc（以下简称 称为 Myc）通过直接反式激活 Gln 转运蛋白 SLC1A5 的表达来增强 Gln 使用 和 SLC7A5/SLC3A2，并通过 GLS1 转录抑制来增加 GLS1 表达 抑制子微小RNA (miR)-23a/b。正在积极研究以 GLS1 为靶点的药理学作为抗 癌症方法，尽管迄今为止收效甚微。另一方面，最近的一些研究，包括 我们实验室的研究指出了谷氨酰胺合成的重要性，至少在某些细胞/组织类型中是这样。谷氨酰胺是 在谷氨酰胺合成酶（GS，也称为谷氨酰胺合成酶）的催化下，通过谷氨酸和氨的缩合从头合成 称为谷氨酸氨连接酶，GLUL）。使用基于稳定同位素的代谢物追踪，我们最近 据报道，这种合成的谷氨酰胺并不通过谷氨酰胺分解来为 TCA 循环提供燃料；相反，它用于 几个不依赖于 TCA 的合成代谢过程，包括核苷酸的生物合成和必需物质的运输 氨基酸。重要的是，GS 表达升高可促进 Gln 限制下的细胞存活。抑制 GS 导致细胞增殖减少，Gln 限制时细胞死亡增加，并减缓异种移植肿瘤 生长。此外，我们最近报道Myc可以诱导多种癌细胞中GS的表达 线。我们还发现几种小鼠模型中 Myc 激活与 GS 表达呈正相关 以及人类患者样本中。这些发现使我们提出以下假设：致癌 Myc， 至少在某些细胞/组织类型中，上调 GS 表达以促进 Gln 产生及其 合成代谢的使用（远离 TCA 循环），从而促进肿瘤发生。我们提出两个具体的 旨在研究这一假设：1）研究代谢和细胞生物学后果，以及 Myc 激活时 GS 表达增加； 2) 确定 GS 在 Myc- 中的体内作用 驱动代谢重编程和肿瘤发生。如果完成，这项研究将提供一个新的维度 了解癌细胞中 Myc 失调的功能以及治疗癌症的潜在新靶点 Myc 驱动的肿瘤。