RRC ID 58852
Author Yamaguchi I, Yoshimura SH, Katoh H.
Title High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11).
Journal J Biol Chem
Abstract The cystine/glutamate transporter system xc- consists of the light-chain 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 GSH, one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species, xCT, responsible for cystine-glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces reactive oxygen species accumulation and cell death. Here we report that cell survival under glucose deprivation depends on cell density. We found that 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 of cells grown at low density with the mTOR inhibitor Torin 1 down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1-treated cells grown at low density. Additionally, bafilomycin A1 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 control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.
Volume 295(20)
Pages 6936-6945
Published 2020-5-15
DOI 10.1074/jbc.RA119.012213
PII S0021-9258(17)48197-X
PMID 32265299
PMC PMC7242691
MeSH Amino Acid Transport System y+ / genetics Amino Acid Transport System y+ / metabolism* Cell Line, Tumor Glioblastoma / genetics Glioblastoma / metabolism* Glioblastoma / pathology Glucose / metabolism* Humans Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Proteolysis*
IF 4.238
Times Cited 1
Human and Animal Cells T98G(RCB1954)