Regulation of Amino-acid Transport in Human Gliomas

项目概要/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 神经胶质瘤1.谷氨酸在肿瘤周围组织中可以达到有毒浓度，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 摄取提供胱氨酸以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源的影响，包括辐射和 化疗。 GSH 过量产生可抵抗辐射 4-6 和铁死亡 7（一种铁依赖性形式） 程序性细胞死亡。在之前的研究中，我们表明 xCT（SXC 的催化亚基）在不同程度上存在 在神经胶质瘤患者中表达8。大约一半的肿瘤显示 xCT 表达升高并存在 具有癫痫发作和 Glu 兴奋性毒性，而 xCT 表达低的神经胶质瘤则没有。同样，在临床试验中 研究表明，SXC 的药理学抑制仅在 xCT 升高的神经胶质瘤中减少 Glu 释放 表达式8.根据最近的数据，我们现在假设 SXC 的表达和功能存在差异 这是由于其转录和辅助受体调节。我们假设 xCT 是转录调控的 由 p53 控制，野生型 p53 充当转录抑制因子。由于p53在许多神经胶质瘤中发生突变或缺失， 这种改变会导致 xCT 异常过度表达，解释了观察到的 Glu 释放和 下游病理生理学。根据初步调查结果，我们还假设 SXC 的活动是 受激活透明质酸受体 CD44 的细胞外基质成分调节，该受体充当 SXC 的功能性辅助受体。 p53 和 CD44 活性均可改变神经胶质瘤生物学并决定瘤周 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，因为它们 探索干扰神经胶质瘤转录和异常谷氨酸生物学的新策略 表达水平。该提案为目前可用的药物抑制剂提供了更好的策略 SXC的特异性和生物利用度较差。此外，p53和CD44的表达可能具有 关于未来该胶质瘤亚组潜在个性化治疗的预测价值。

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.