Data from Increased Expression of System x_c⁻ in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Abstract

<div>Abstract<p>Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (<i>SLC7A11</i>), the catalytic subunit of system x<sub>c</sub><sup>−</sup>, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system x<sub>c</sub><sup>−</sup> in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system x<sub>c</sub><sup>−</sup> with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system x<sub>c</sub><sup>−</sup> in glioma, stable <i>SLC7A11</i>-knockdown and -overexpressing U251 glioma cells were generated. Modulation of <i>SLC7A11</i> did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of <i>SLC7A11</i> increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of <i>SLC7A11</i> resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, <i>SLC7A11</i> overexpression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation, and ATP generation. These results suggest that expression of <i>SLC7A11</i> in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy.</p><p><b>Implications:</b> <i>SLC7A11</i>, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system x<sub>C</sub><sup>−</sup> a potential therapeutic target in glioblastoma multiforme. <i>Mol Cancer Res; 14(12); 1229–42. ©2016 AACR</i>.</p></div>