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: 10321925
• 负责人: HARALD W SONTHEIMER
• 金额: $ 36.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321925
• 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; 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.

项目总结/摘要 谷氨酸（Glu）已成为恶性脑肿瘤生物学中的重要分子，特别是 胶质瘤1. Glu可在肿瘤周围组织中达到毒性浓度，有助于增强肿瘤生长， 侵袭以及瘤周水肿、兴奋性毒性和癫痫发作2。由胱氨酸-谷氨酸介导 交换器，系统xc-（SXC），Glu摄取提供胱氨酸用于产生细胞内抗氧化剂 谷胱甘肽（GSH）。GSH保护细胞免受内源性和外源性应激物3，包括辐射和 化疗GSH的过量生产赋予了对辐射的抵抗力4 -6和铁中毒7，一种依赖铁的形式 程序性细胞死亡在以前的研究中，我们发现SXC的催化亚基xCT是一个双链的， 在胶质瘤患者中表达8.大约一半的肿瘤显示xCT表达升高， 具有癫痫发作和Glu兴奋性毒性，而具有低xCT表达的胶质瘤则没有。同样，在临床试验中， 研究表明，药理学抑制SXC仅在xCT升高的胶质瘤中减少Glu释放 表情8.基于最近的数据，我们现在假设SXC的表达和功能的差异， 是由于其转录和共受体调节。我们假设xCT是转录调控的， p53，野生型p53作为转录抑制因子。由于p53在许多神经胶质瘤中突变或缺失， 这种改变将导致xCT的异常过表达，解释了观察到的Glu释放， 下游病理生理学我们还假设，根据初步的研究结果，SXC的活动是 受细胞外基质成分的调节，激活透明质酸受体CD 44，其作为一种免疫调节因子。 SXC的功能性共受体。p53和CD 44活性都可以改变胶质瘤生物学，并决定肿瘤周围的 兴奋性毒性、癫痫发作、侵袭和生长。拟议的研究具有重要意义和临床相关性，因为 探索新的策略来干扰神经胶质瘤的异常谷氨酸生物学的转录， 表达水平。该建议提供了优于目前可用的药理学抑制剂的上级策略，用于 SXC的特异性和生物利用度较差。此外，p53和CD 44的表达可能与 预测价值的潜在个性化治疗这一亚组的胶质瘤在未来。