The radio-sensitizing effect and tumor growth inhibition by cystine glutamate transporter (system xc-) inhibition in glioblastoma

Abstract

Glioblastoma is the most aggressive brain tumor. Despite existing multimodal therapy, new therapeutic strategies are required. System xc-, composed of a light-chain subunit (xCT, SLC7A11) and a heavy chain subunit (CD98hc, SLC3A2), releases glutamate outside the cell and concurrently uptakes cystine in the cell at a 1 to 1 ratio. The increased intracellular cystine, due to uptake by system xc-, is transformed into glutathione (GSH) that is one of the most important antioxidants in cancer cells, contributing to cancer cell survival and proliferation. So, I investigated that the inhibition of system xc- could improve the radio-sensitivity and reduce the cell growth and migration in glioblastoma.

Herein, I show that system xc- inhibition could enhance radio-sensitivity and repress glioblastoma progression and invasion. System xc- inhibition induces a decrease in intracellular GSH in glioblastoma. Irradiation combined with system xc- inhibition increases DNA double strand breaks (DSB) than that with irradiation alone in glioblastoma. The combination of irradiation and system xc- inhibition resulted in a significantly lower surviving fraction at each dose than irradiation alone.

Irradiation could induce the change of mesenchymal markers. Additionally, the expression of the Cancer Genome Atlas (TCGA)-based markers of mesenchymal glioblastoma, CD44 and YKL-40, was elevated after the irradiation. System xc- inhibition reduced cell migration through the change of mesenchymal markers in glioblastoma. Although irradiation significantly increased cell movement, system xc- inhibition blocked the radiation-induced cell migration. System xc- inhibition is significantly related to decrease in mesenchymal markers, including SNAIL, vimentin, N-cadherin, alpha-SMA and FAP in glioblastoma. System xc- protein expression was significantly higher in the mesenchymal than that in the proneural human glioblastoma specimens.

In conclusion, these findings demonstrate that system xc- inhibition in combination with irradiation could decrease cystine uptake and GSH, inducing an increase in DNA DSB. System xc- inhibition could enhance radio-sensitivity in glioblastoma. In addition, system xc- inhibition prevented the radiation-induced cell migration and affected mesenchymal features, which are adverse prognostic factors in glioblastoma. Taken together, my results indicate that the combination of radiation therapy (RT) and system xc- inhibition could improve therapeutic outcomes in glioblastoma.