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.

项目摘要/摘要 谷氨酸(Glu)已成为恶性脑肿瘤生物学中的重要分子，尤其是 胶质瘤1。谷氨酸可在肿瘤周围组织中达到有毒浓度，有助于促进肿瘤生长和 侵袭，以及瘤周水肿、兴奋性毒性和癫痫2。由半胱氨酸-谷氨酸介导 交换系统XC-(SXC)，Glu摄取为细胞内抗氧化剂的生产提供半胱氨酸 谷胱甘肽(GSH)GSH保护细胞免受内源性和外源性压力，包括辐射和 化疗。GSH的过量生产使人对辐射4-6和铁中毒7具有抵抗力，这是一种依赖铁的形式 程序性细胞死亡。在以前的研究中，我们证明了SXC的催化亚基XCT是可变的 在胶质瘤患者中表达。大约一半的肿瘤显示XCT表达升高并存在 与癫痫发作和谷氨酸兴奋毒性有关，而XCT低表达的胶质瘤则没有。同样，在一项临床试验中 研究表明，SXC的药理抑制只在XCT升高的胶质瘤中减少Glu的释放 表情8。根据最近的数据，我们现在假设SXC的表达和功能的差异 是由于它的转录和共同受体的调节。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在许多胶质瘤中发生突变或缺失， 这种改变会导致XCT的异常过表达，解释了观察到的Glu释放和 下游的病理生理学。我们还假设，根据初步发现，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，CD44作为一种 SXC的功能性共受体。P53和CD44活性均可改变胶质瘤生物学行为并确定瘤周 兴奋性毒性、癫痫发作、入侵和生长。拟议的研究具有重要意义和临床意义，因为它们 探索在转录和转录水平干扰脑胶质瘤谷氨酸异常生物学的新策略 表达式级别。这一建议提供了优于目前可用的药物抑制剂的策略 SXC的特异性和生物利用度较差。此外，P53和CD44的表达可能有 对未来这一亚组胶质瘤的潜在个体化治疗的预测价值。