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

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.

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

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.

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