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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

基本信息

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
项目类别：
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

项目摘要

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.

总结