GAD1 ameliorates glioma progression through regulating cuproptosis via RAS/MAPK pathway

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biochemical and Molecular Toxicology Pub Date : 2024-09-12 DOI:10.1002/jbt.23848

Zhiqiang Gao, Jing Yang

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Abstract

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.

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GAD1 通过 RAS/MAPK 通路调控杯突变化，从而改善胶质瘤的发展进程

胶质瘤是发生在中枢神经系统的一种原发性恶性肿瘤。谷氨酸脱羧酶（GAD1）在肿瘤发生发展过程中起着重要作用；然而，GAD1的功能及其在胶质瘤发展过程中的潜在机制仍不清楚。研究人员采用综合生物信息学方法，从 GSE12657 和 GSE15209 数据集中获得了与杯突症相关基因和枢轴基因有交叉的差异表达基因（DEGs）。通过检测细胞内铜水平和杯突症标志物的表达，验证了伊利司莫（ES）处理可诱导 U251 细胞发生杯突症。研究人员利用慢病毒介导的基因过表达，在体外和小鼠异种移植模型中进行功能测试，以探索 GAD1 的作用。RAS 激动剂 ML098 被用来验证 GAD1 对胶质瘤细胞中 RAS/MAPK 通路的影响。共获得了87个杯突症相关的DEGs和7个枢纽基因，其中5个基因在胶质瘤中上调，2个基因下调。过表达 GAD1 可抑制胶质瘤细胞的增殖、侵袭和迁移，促进凋亡，抑制体内肿瘤发生。此外，GAD1 的过表达增强了胶质瘤细胞对杯突症的敏感性。此外，ML098 处理可减轻 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通路调节细胞凋亡，从而在胶质瘤中发挥抗癌作用。

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来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.