Role of ferritinophagy in cystine deprivation-induced cell death in glioblastoma cells
Role of ferritinophagy in cystine deprivation-induced cell death in glioblastoma cells
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DOI：
10.1016/j.bbrc.2020.12.075
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发表时间：
2021-01-06
影响因子：
3.1
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
--
作者：
Hayashima, Kazuki;Kimura, Ikuo;Katoh, Hironori
铁下垂是一种由铁依赖性脂质过氧化引起的细胞死亡。癌细胞增加胱氨酸的摄取，以合成谷胱甘肽（GSH），谷胱甘肽过氧化物酶4利用胱甘肽过氧化物来减少脂质过氧化物。在这里，我们报道了胶质母细胞瘤细胞中的胱氨酸剥夺，而不是l -丁硫氨酸亚砜（BSO）对GSH合成的抑制，诱导铁凋亡。我们发现，胱氨酸剥夺降低了铁蛋白重链FTH1的蛋白水平，而BSO处理则升高了。溶酶体抑制剂巴菲霉素A1或核受体共激活因子4 （NCOA4）的缺失抑制胱氨酸剥夺引起的FTH1蛋白水平下降和细胞死亡。此外，胱氨酸剥夺诱导微管相关蛋白轻链3 (LC3)-II蛋白积累，提示胱氨酸剥夺诱导铁蛋白自噬。当胶质母细胞瘤细胞用铁诱导剂、硫酸铵亚铁或血红蛋白处理时，BSO引起细胞死亡。另一方面，胱氨酸剥夺诱导的FTH1降解和细胞死亡需要谷氨酰胺。本研究提示，除了GSH耗竭外，铁蛋白自噬在半胱氨酸剥夺诱导的胶质母细胞瘤细胞铁凋亡中起重要作用。(C) 2020爱思唯尔公司版权所有。
Ferroptosis is a form of cell death caused by iron-dependent lipid peroxidation. Cancer cells increase cystine uptake for the synthesis of glutathione (GSH), which is used by glutathione peroxidase 4 to reduce lipid peroxides. Here, we report that cystine deprivation in glioblastoma cells, but not inhibition of GSH synthesis by L-buthionine sulfoximine (BSO), induces ferroptosis. We found that cystine deprivation decreased the protein levels of ferritin heavy chain FTH1, whereas it was increased by BSO treatment. The lysosome inhibitor bafilomycin A1 or deletion of nuclear receptor coactivator 4 (NCOA4) inhibited cystine deprivation-induced decrease in FTH1 protein levels and cell death. In addition, cystine deprivation induced microtubule-associated protein light chain 3 (LC3)-II protein accumulation, suggesting that cystine deprivation induces ferritinophagy. BSO causes cell death when glioblastoma cells are treated with iron inducers, ferrous ammonium sulfate or hemin. On the other hand, cystine deprivation-induced degradation of FTH1 and cell death required glutamine. This study suggests that ferritinophagy, in addition to GSH depletion, plays an important role in cystine deprivation-induced ferroptosis in glioblastoma cells. (C) 2020 Elsevier Inc. All rights reserved.