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タイトル: | High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11) |
著者: | Yamaguchi, Itsuki Yoshimura, Shige H. Katoh, Hironori https://orcid.org/0000-0002-8191-8117 (unconfirmed) |
著者名の別形: | 山口, 一樹 吉村, 成弘 加藤, 裕教 |
キーワード: | amino acid transport cell death cancer biology cell biology lysosome |
発行日: | 15-May-2020 |
出版者: | American Society for Biochemistry and Molecular Biology Inc. |
誌名: | Journal of Biological Chemistry |
巻: | 295 |
開始ページ: | 6936 |
終了ページ: | 6945 |
抄録: | The cystine/glutamate transporter system x c − 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. |
著作権等: | This research was originally published in the Journal of Biological Chemistry. [Itsuki Yamaguchi, Shige H. Yoshimura. Hironori Katoh. High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11). J. Biol. Chem. 2020; 295: 6936-6945].© 2020 Yamaguchi et al. The full-text file will be made open to the public on 15 May 2021 in accordance with publisher's 'Terms and Conditions for Self-Archiving' |
URI: | http://hdl.handle.net/2433/252465 |
DOI(出版社版): | 10.1074/jbc.RA119.012213 |
PubMed ID: | 32265299 |
出現コレクション: | 学術雑誌掲載論文等 |
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