High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11)
High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11)
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DOI：
10.1074/jbc.ra119.012213
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发表时间：
2020-05-15
影响因子：
4.8
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
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作者：
Yamaguchi, Itsuki;Yoshimura, Shige H.;Katoh, Hironori
胱氨酸/谷氨酸转运系统 xc？由轻链亚基 xCT (SLC7A11) 和重链亚基 CD98 (4F2hc 或 SLC3A2) 组成，并在质膜上将细胞外胱氨酸交换为细胞内谷氨酸。输入的胱氨酸被还原为半胱氨酸并用于合成谷胱甘肽（GSH），谷胱甘肽是癌细胞中最重要的抗氧化剂之一。由于癌细胞的活性氧水平升高，负责胱氨酸-谷氨酸交换的 xCT 在许多癌症（包括胶质母细胞瘤）中过度表达。然而，在葡萄糖限制条件下，xCT 过度表达会诱导活性氧积累和细胞死亡。在这里，我们报告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) 会下调 xCT 水平并增加葡萄糖剥夺下的细胞活力。我们还发现，HD 下胶质母细胞瘤细胞的生长会使 mTOR 失活，并且用 mTOR 抑制剂 Torin 1 处理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。溶酶体抑制剂巴弗洛霉素 A1 抑制 HD 培养的胶质母细胞瘤细胞和低密度生长的 Torin 1? 处理细胞中 xCT 的下调。此外，巴弗洛霉素 A1 暴露或异位 xCT 表达可恢复 HD 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，从而提高葡萄糖限制条件下胶质母细胞瘤细胞的活力。我们的研究结果证明，通过溶酶体降解控制 xCT 蛋白表达是胶质母细胞瘤细胞代谢适应的重要机制。
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.