Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Cell Signal. 2021 Feb;78:109874. doi: 10.1016/j.cellsig.2020.109874. Epub 2020 Dec 5.
The cystine/glutamate antiporter xCT (SLC7A11) is frequently overexpressed in many cancers, including glioblastoma. Cystine taken up by the cells via xCT is reduced to cysteine, which is used to synthesize glutathione for antioxidant cellular defense. However, overexpression of xCT causes cell death under glucose-limited conditions. We found that stimulation of glioblastoma cells with epidermal growth factor (EGF) induces the upregulation of xCT and promotes cell death under glucose deprivation. Treatment with the mTOR inhibitor Torin 1 suppressed the EGF-induced upregulation of xCT and cell death. EGF increased xCT mRNA levels, which was suppressed by Torin 1. The lysosome inhibitor bafilomycin A1 increased xCT protein levels in the absence of EGF or in the presence of EGF and Torin 1. Taken together, our study suggests that EGF promotes glioblastoma cell death under glucose-limited conditions via the upregulation of xCT at transcriptional and protein levels in an mTOR-dependent manner.
胱氨酸/谷氨酸反向转运蛋白 xCT（SLC7A11）在许多癌症中经常过表达，包括神经胶质瘤。细胞通过 xCT 摄取的胱氨酸被还原为半胱氨酸，半胱氨酸用于合成谷胱甘肽以进行抗氧化细胞防御。然而，xCT 的过表达会导致葡萄糖限制条件下的细胞死亡。我们发现，表皮生长因子（EGF）刺激神经胶质瘤细胞会诱导 xCT 的上调，并促进葡萄糖剥夺下的细胞死亡。用 mTOR 抑制剂 Torin 1 处理可抑制 EGF 诱导的 xCT 上调和细胞死亡。EGF 增加了 xCT mRNA 水平，而 Torin 1 则抑制了这种作用。溶酶体抑制剂巴弗洛霉素 A1 可增加无 EGF 或存在 EGF 和 Torin 1 时的 xCT 蛋白水平。总之，我们的研究表明，EGF 通过 mTOR 依赖性方式在转录和蛋白水平上上调 xCT，从而促进葡萄糖限制条件下神经胶质瘤细胞的死亡。
