Regulation of Amino-acid Transport in Human Gliomas

人类神经胶质瘤中氨基酸运输的调节

• 批准号: 10064133
• 负责人: HARALD W SONTHEIMER
• 金额: $ 14.02万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064133
• 关键词: Amino Acids; Antioxidants; Apoptosis; Binding; Binding Sites; Biological; Biological Assay; Biological Availability; Biology; Blood Vessels; Brain; CD44 Antigens; CD44 gene; Catalytic Domain; Cells; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Cystine; DNA Binding Domain; Data; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disease; Drug Kinetics; Edema; Extracellular Matrix; Free Radicals; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Glioma; Glutamates; Glutathione; Growth; Human; Hyaluronan; Hyaluronic Acid; Institutional Review Boards; Iron; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Measures; Mediating; Membrane; Mutate; Mutation; Patients; Pharmacology; Phenotype; Physiological; Pilot Projects; Predictive Value; Production; Regulation; Resistance; Role; Seizures; Slice; Small Interfering RNA; Specificity; Subgroup; System; TP53 gene; Testing; Tetanus Helper Peptide; Tissues; Transcriptional Regulation; Tumor Cell Invasion; Viral; Western Blotting; base; chromatin immunoprecipitation; clinically relevant; excitotoxicity; in vivo; inhibitor/antagonist; knock-down; mutant; mutational status; novel; overexpression; personalized medicine; prevent; promoter; prospective; receptor; restoration; small hairpin RNA; stem cells; tumor; tumor growth; uptake

Project Summary/Abstract Glutamate (Glu) has emerged as an important molecule in the biology of malignant brain tumors, specifically gliomas1. Glu can reach toxic concentrations in peritumoral tissue, contributing to enhanced tumor growth and invasion, as well as peritumoral edema, excitotoxicity, and seizures2. Mediated by the cystine-glutamate exchanger, System xc- (SXC), Glu uptake supplies cystine for production of the intracellular antioxidant glutathione (GSH). GSH protects cells from endogenous and exogenous stressors3, including radiation and chemotherapy. GSH over-production confers resistance to radiation4-6 and ferroptosis7, an iron-dependent form of programmed cell death. In previous studies, we show that xCT, the catalytic subunit of SXC, is variably expressed among glioma patients8. Approximately half of tumors show elevated xCT expression and present with seizures and Glu excitotoxicity, whereas gliomas with low xCT expression do not. Similarly, in a clinical pilot study, we show that pharmacological inhibition of SXC reduces Glu release only in gliomas with elevated xCT expression8. Based on recent, data we now hypothesize that differences in the expression and function of SXC are due to its transcriptional and co-receptor regulation. We hypothesize that xCT is transcriptionally regulated by p53, with wild type p53 acting as transcriptional suppressor. As p53 is mutated or deleted in many gliomas, this alteration would result in aberrant overexpression of xCT, explaining the observed Glu release and downstream pathophysiology. We also hypothesize, based on preliminary findings, that the activity of SXC is regulated by extracellular matrix components activating the hyaluronic acid receptor CD44, which serves as a functional co-receptor for SXC. Both p53 and CD44 activity can alter glioma biology and determine peritumoral excitotoxicity, seizures, invasion, and growth. The proposed studies are significant and clinically relevant as they explore new strategies to interfere with the abnormal glutamate biology of gliomas at a transcription and expression level. This proposal provides superior strategies to currently available pharmacological inhibitors for SXC, which have poor specificity and bioavailability. Moreover, the expression of p53 and CD44 may have predictive value regarding potential personalized treatments for this subgroup of glioma in the future.

项目摘要/摘要 谷氨酸（GLU）已成为恶性脑肿瘤生物学的重要分子，特别是 Gliomas1。 GLU可以在周围组织中达到毒性浓度，从而导致肿瘤生长的增长和 入侵以及周围水肿，兴奋性和癫痫发作2。由胱氨酸 - 谷氨酸介导 交换器，系统XC-（SXC），Glu摄取供应Cystine用于生产细胞内抗氧化剂 谷胱甘肽（GSH）。 GSH可保护细胞免受内源性和外源性应激剂3的影响，包括辐射和 化学疗法。 GSH生产过多赋予对辐射4-6和铁吞作用的抗性7（一种依赖铁的形式） 程序性细胞死亡。在先前的研究中，我们表明XCT是SXC的催化亚基，是可变的 在神经胶质瘤患者中表达8。大约一半的肿瘤表现出升高的XCT表达和存在 具有癫痫发作和GLU兴奋性毒性，而XCT表达低的胶质瘤则没有。同样，在临床飞行员中 研究，我们表明，SXC的药理抑制仅在XCT升高的神经胶质瘤中降低GLU释放 表达式8。根据最近的数据，我们现在假设SXC的表达和功能差异 是由于其转录和共受体调节。我们假设XCT是经转录调节的 由p53，野生型p53充当转录抑制器。由于p53在许多神经胶质瘤中被突变或删除，因此 这种改变会导致XCT异常表达，从而解释了观察到的GLU释放和 下游病理生理学。我们还根据初步发现假设SXC的活性是 由激活透明质酸受体CD44的细胞外基质成分调节 SXC的功能共受体。 p53和CD44活性都可以改变神经胶质瘤生物学并确定周围 兴奋性，癫痫发作，入侵和生长。拟议的研究很重要，并且在临床上是相关的 探索新的策略，以干扰转录时神经胶质瘤异常的谷氨酸生物学 表达水平。该建议为当前可用的药理学抑制剂提供了卓越的策略 SXC，特异性和生物利用度较差。此外，p53和CD44的表达可能具有 未来这种神经胶质瘤亚组的潜在个性化处理的预测价值。