Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
J Biol Chem. 2022 Mar;298(3):101703. doi: 10.1016/j.jbc.2022.101703. Epub 2022 Feb 8.
Ferroptosis is an iron-dependent mode of cell death caused by excessive oxidative damage to lipids. Lipid peroxidation is normally suppressed by glutathione peroxidase 4, which requires reduced glutathione. Cystine is a major resource for glutathione synthesis, especially in cancer cells. Therefore, cystine deprivation or inhibition of cystine uptake promotes ferroptosis in cancer cells. However, the roles of other molecules involved in cysteine deprivation-induced ferroptosis are unexplored. We report here that the expression of gamma-glutamyltransferase 1 (GGT1), an enzyme that cleaves extracellular glutathione, determines the sensitivity of glioblastoma cells to cystine deprivation-induced ferroptosis at high cell density (HD). In glioblastoma cells expressing GGT1, pharmacological inhibition or deletion of GGT1 suppressed the cell density-induced increase in intracellular glutathione levels and cell viability under cystine deprivation, which were restored by the addition of cysteinylglycine, the GGT product of glutathione cleavage. On the other hand, cystine deprivation induced glutathione depletion and ferroptosis in GGT1-deficient glioblastoma cells even at an HD. Exogenous expression of GGT1 in GGT1-deficient glioblastoma cells inhibited cystine deprivation-induced glutathione depletion and ferroptosis at an HD. This suggests that GGT1 plays an important role in glioblastoma cell survival under cystine-limited and HD conditions. We conclude that combining GGT inhibitors with ferroptosis inducers may provide an effective therapeutic approach for treating glioblastoma.
铁死亡是一种由脂质过度氧化损伤引起的铁依赖性细胞死亡模式。谷胱甘肽过氧化物酶 4 通常会抑制脂质过氧化，而谷胱甘肽过氧化物酶 4 需要还原型谷胱甘肽。胱氨酸是合成谷胱甘肽的主要资源，尤其是在癌细胞中。因此，剥夺胱氨酸或抑制胱氨酸摄取会促进癌细胞发生铁死亡。然而，其他参与胱氨酸剥夺诱导铁死亡的分子的作用仍未被探索。我们在这里报告，γ-谷氨酰转移酶 1（GGT1）的表达，一种能裂解细胞外谷胱甘肽的酶，决定了神经胶质瘤细胞在高密度（HD）下对胱氨酸剥夺诱导的铁死亡的敏感性。在表达 GGT1 的神经胶质瘤细胞中，GGT1 的药理学抑制或缺失抑制了胱氨酸剥夺下细胞密度诱导的细胞内谷胱甘肽水平和细胞活力的增加，而添加谷氨酰半胱氨酸（谷胱甘肽裂解的 GGT 产物）则恢复了这一增加。另一方面，即使在 HD 条件下，胱氨酸剥夺也会诱导 GGT1 缺陷的神经胶质瘤细胞发生谷胱甘肽耗竭和铁死亡。在 GGT1 缺陷的神经胶质瘤细胞中外源性表达 GGT1 会抑制胱氨酸剥夺诱导的谷胱甘肽耗竭和铁死亡。这表明 GGT1 在胱氨酸有限和 HD 条件下对神经胶质瘤细胞的存活起着重要作用。我们得出结论，将 GGT 抑制剂与铁死亡诱导剂联合使用可能为治疗神经胶质瘤提供一种有效的治疗方法。
