Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis.
Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis.
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DOI：
10.1016/j.jbc.2022.101703
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Katoh H
中科院分区：
文献类型：
--
作者：
Hayashima K;Katoh H
铁凋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。脂质过氧化通常被谷胱甘肽过氧化物酶4抑制，这需要还原型谷胱甘肽。胱氨酸是谷胱甘肽合成的主要来源，特别是在癌细胞中。因此，胱氨酸剥夺或胱氨酸摄取的抑制促进癌细胞中的铁凋亡。然而，参与半胱氨酸剥夺诱导的铁凋亡的其他分子的作用尚未探索。我们在这里报告，γ-谷氨酰转移酶1（GGT 1），一种酶，裂解细胞外谷胱甘肽的表达，决定了胶质母细胞瘤细胞的敏感性胱氨酸剥夺诱导的铁凋亡在高细胞密度（HD）。在表达GGT 1的胶质母细胞瘤细胞中，药物抑制或删除GGT 1抑制细胞密度诱导的细胞内谷胱甘肽水平增加和胱氨酸剥夺下的细胞活力，通过添加半胱氨酰甘氨酸（谷胱甘肽裂解的GGT产物）恢复。另一方面，胱氨酸剥夺诱导谷胱甘肽耗竭和铁凋亡在GGT 1缺陷的胶质母细胞瘤细胞，即使在HD。在GGT 1缺陷的胶质母细胞瘤细胞中外源性表达GGT 1抑制了HD时胱氨酸剥夺诱导的谷胱甘肽耗竭和铁凋亡。这表明GGT 1在胱氨酸限制和HD条件下的胶质母细胞瘤细胞存活中起重要作用。我们的结论是，GGT抑制剂与铁凋亡诱导剂相结合，可能为治疗胶质母细胞瘤提供一种有效的治疗方法。
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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
3.3
作者：
Katoh Y;Michisaka S;Nozaki S;Funabashi T;Hirano T;Takei R;Nakayama K
通讯作者：
Nakayama K
影响因子：
3.8
作者：
Kawakami K;Fujita Y;Matsuda Y;Arai T;Horie K;Kameyama K;Kato T;Masunaga K;Kasuya Y;Tanaka M;Mizutani K;Deguchi T;Ito M
通讯作者：
Ito M
影响因子：
15.9
作者：
Dolecek, Therese A.;Propp, Jennifer M.;Kruchko, Carol
通讯作者：
Kruchko, Carol
DOI：
10.1073/pnas.75.11.5405
发表时间：
1978-01-01
影响因子：
11.1
作者：
GRIFFITH, OW;BRIDGES, RJ;MEISTER, A
通讯作者：
MEISTER, A