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High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11).
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2020-04-07 , DOI: 10.1074/jbc.ra119.012213
Itsuki Yamaguchi 1 , Shige H Yoshimura 2 , Hironori Katoh 3
Affiliation  

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.

中文翻译:

高细胞密度可通过胱氨酸/谷氨酸转运蛋白xCT(SLC7A11)降解来增加胶质母细胞瘤在葡萄糖剥夺下的细胞活力。

胱氨酸/谷氨酸转运蛋白系统xc-由轻链亚基xCT(SLC7A11)和重链亚基CD98(4F2hc或SLC3A2)组成,并将胞外胱氨酸在质膜上交换为胞内谷氨酸。进口的胱氨酸还原为半胱氨酸,用于合成GSH,GSH是癌细胞中最重要的抗氧化剂之一。由于癌细胞中活性氧的含量增加,因此负责胱氨酸-谷氨酸交换的xCT在包括胶质母细胞瘤在内的许多癌症中均过表达。但是,在葡萄糖受限的条件下,xCT的过表达诱导了活性氧的积累和细胞死亡。在这里我们报道葡萄糖剥夺下的细胞存活取决于细胞密度。我们发现高细胞密度(HD)下调xCT水平并增加葡萄糖剥夺下的细胞活力。我们还发现,胶质母细胞瘤细胞在HD的生长会失活mTOR,而以mTOR抑制剂Torin 1低密度生长的细胞会下调xCT并抑制葡萄糖剥夺诱导的细胞死亡。溶酶体抑制剂bafilomycin A1抑制了HD培养的成胶质母细胞瘤细胞和低密度生长的Torin 1处理的细胞中xCT的下调。此外,bafilomycin A1暴露或异位xCT表达可恢复高清时葡萄糖剥夺诱导的细胞死亡。这些结果表明,HD使mTOR失活并促进xCT的溶酶体降解,从而在葡萄糖受限的条件下改善了胶质母细胞瘤细胞的生存能力。
更新日期:2020-05-15
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