Department of Neurosurgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
J Biochem Mol Toxicol. 2024 Oct;38(10):e23848. doi: 10.1002/jbt.23848.
Glioma represents a primary malignant tumor occurring in the central nervous system. Glutamate decarboxylase (GAD1) plays a significant role in tumor development; however, its function of GAD1 and underlying mechanisms in glioma progression remain unclear. Differentially expressed genes (DEGs) obtained from the GSE12657 and GSE15209 datasets that intersected with cuproptosis-related genes and pivot genes were identified using comprehensive bioinformatics methods. The elesclomol (ES) treatment was used to induce cuproptosis in U251 cells, which was validated by detecting intracellular copper levels and cuproptosis marker expression. Lentivirus-mediated gene overexpression was performed to explore the effects of GAD1 using functional assays in vitro and in a mouse xenograft model. The RAS agonist ML098 was used to verify the effect of GAD1 on the RAS/MAPK pathway in glioma cells. A total of 87 cuproptosis-related DEGs and seven hub genes were obtained, with five genes upregulated and two were downregulated in gliomas. Overexpression of GAD1 inhibited proliferation, invasion, and migration, promoted apoptosis of glioma cells, and suppressed tumorigenesis in vivo. In addition, GAD1 overexpression enhanced the sensitivity of glioma cells to cuproptosis. Additionally, ML098 treatment attenuated the inhibitory effect of GAD1 overexpression on the malignant phenotype of ES-treated cells. GAD1 plays an anti-oncogenic role in glioma by regulating apoptosis via inhibition of the RAS/MAPK pathway.
神经胶质瘤是一种发生于中枢神经系统的原发性恶性肿瘤。谷氨酸脱羧酶（GAD1）在肿瘤发生发展中起重要作用，但 GAD1 的功能及其在神经胶质瘤进展中的潜在机制尚不清楚。综合生物信息学方法，从 GSE12657 和 GSE15209 数据集获得与铜死亡相关基因和枢纽基因相交的差异表达基因（DEGs）。采用 elesclomol（ES）诱导 U251 细胞发生铜死亡，并通过检测细胞内铜水平和铜死亡标志物表达进行验证。采用慢病毒介导的基因过表达技术，体外和小鼠异种移植模型中进行功能实验，探讨 GAD1 的作用。采用 RAS 激动剂 ML098 验证 GAD1 对神经胶质瘤细胞中 RAS/MAPK 通路的影响。共获得 87 个与铜死亡相关的 DEGs 和 7 个枢纽基因，其中 5 个基因在神经胶质瘤中上调，2 个基因下调。过表达 GAD1 抑制了神经胶质瘤细胞的增殖、侵袭和迁移，促进了细胞凋亡，并抑制了体内肿瘤发生。此外，过表达 GAD1 增强了神经胶质瘤细胞对铜死亡的敏感性。此外，ML098 处理减弱了 GAD1 过表达对 ES 处理细胞恶性表型的抑制作用。GAD1 通过抑制 RAS/MAPK 通路调控细胞凋亡，在神经胶质瘤中发挥抑癌作用。
