Induction of glioblastoma invasion triggered by system Xc−-mediated glutamate release

IF 1.1 4区医学 Q4 TOXICOLOGY Molecular & Cellular Toxicology Pub Date : 2024-03-07 DOI:10.1007/s13273-024-00433-x

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Abstract

Backgrounds

Glioblastoma (GBM) is a highly aggressive brain cancer associated with poor prognosis, primarily attributed to its profound invasive characteristics. Glutamate is the main cause of invasion, and invasion is promoted by system Xc⁻ (cystine/glutamate antiporter), which is highly expressed in GBM. To date, no studies have examined the relationship between invasion and the specific downregulation of system Xc⁻ (xCT or SLC7A11) using shRNA in GBM.

Objective

We aimed to determine the effect of a specific knockdown system, Xc⁻, in GBM using short hairpin RNA (shRNA) rather than pharmacological approaches.

Results

Invasion was inhibited in GBM cells treated with sulfasalazine, a system Xc⁻ inhibitor. Our experiments validated a reduction in extracellular glutamate concentration following sulfasalazine treatment, without affecting GBM proliferation or calcium response. However, the efficacy of pharmacological methods is hindered by nonspecific effects and the prevalence of multiple side effects. Therefore, we specifically targeted the system Xc⁻ molecule through shRNA. Downregulation using shRNA demonstrated decreased invasion and extracellular glutamate levels, without affecting the calcium response and proliferation.

Conclusion

The targeted inhibition of system Xc⁻ using shRNA yields a notable reduction in GBM invasion.

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Xc系统介导的谷氨酸释放诱发胶质母细胞瘤侵袭

摘要背景胶质母细胞瘤（GBM）是一种侵袭性很强的脑癌，预后很差，这主要归因于它具有很强的侵袭性。谷氨酸是造成侵袭的主要原因，而胱氨酸/谷氨酸拮抗剂系统 Xc- （胱氨酸/谷氨酸拮抗剂）可促进侵袭，该系统在 GBM 中高度表达。迄今为止，还没有研究探讨了侵袭与使用 shRNA 在 GBM 中特异性下调系统 Xc-（xCT 或 SLC7A11）之间的关系。目的我们旨在利用短发夹 RNA（shRNA）而非药理学方法确定特异性下调系统 Xc- 对 GBM 的影响。结果用磺胺沙拉嗪（一种 Xc- 系统抑制剂）处理的 GBM 细胞的侵袭受到抑制。我们的实验证实，磺胺沙拉嗪处理后细胞外谷氨酸浓度降低，但不影响 GBM 的增殖或钙反应。然而，药理学方法的疗效受到非特异性效应和多种副作用的阻碍。因此，我们通过 shRNA 特异性地靶向系统 Xc- 分子。使用 shRNA 进行下调后，侵袭和细胞外谷氨酸水平均有所下降，但不影响钙反应和增殖。结论使用 shRNA 对系统 Xc- 进行靶向抑制可显著减少 GBM 的侵袭。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular & Cellular Toxicology 医学-毒理学

CiteScore

2.50

自引率

17.60%

发文量

114

审稿时长

6-12 weeks

期刊介绍： Molecular & Cellular Toxicology publishes original research and reviews in all areas of the complex interaction between the cell´s genome (the sum of all genes within the chromosome), chemicals in the environment, and disease. Acceptable manuscripts are the ones that deal with some topics of environmental contaminants, including those that lie in the domains of analytical chemistry, biochemistry, pharmacology and toxicology with the aspects of molecular and cellular levels. Emphasis will be placed on toxic effects observed at relevant genomics and proteomics, which have direct impact on drug development, environment health, food safety, preventive medicine, and forensic medicine. The journal is committed to rapid peer review to ensure the publication of highest quality original research and timely news and review articles.