High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11).

The the cystine/glutamate transporter system xc subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of glutathione, which is one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species (ROS), xCT, being responsible for cystine-glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces ROS accumulation and cell death. Here, we report that cell survival under glucose deprivation depends on cell density. We found that a high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR, and that treatment with the mTOR inhibitor Torin 1 of cells grown at low density (LD) down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 (BafA1) suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1-treated cells grown at LD. Additionally, BafA1 exposure or ectopic xCT expression restored glucose deprivation-induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that the control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.