School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
Biochem Biophys Res Commun. 2020 Apr 30;525(2):366-371. doi: 10.1016/j.bbrc.2020.02.093. Epub 2020 Feb 21.
Ferroptosis is a form of regulated cell death induced by lipid peroxidation that is dependent on iron. This pathway is being considered as an alternative anticancer therapeutic strategy, and the chemoreagent erastin induces ferroptosis by blocking system Xc, which causes a cysteine shortage that depletes intracellular GSH. Mitochondrial NADP-dependent isocitrate dehydrogenase (IDH2) is major enzyme that produces NADPH, which is a crucial source for mitochondrial GSH turnover. Therefore, we hypothesized that down-regulation of IDH2 would have a synergic effect on erastin-induced ferroptosis. Here, we investigated the effect of IDH2 knockdown on ferroptosis in human HT1080 fibrosarcoma and murine Hepa1-6 hepatoma cells cultured in vitro as well as in an in vivo model of allografted Hepa1-6 cells in nude mice. Our results show that susceptibility to ferroptosis was substantially increased when IDH2 was down-regulated. This study supports that IDH2 has protective effect against ferroptotic cell death, and that the enzyme could be targeted to sensitize cancer cells to ferroptosis.
铁死亡是一种依赖于铁的脂质过氧化诱导的细胞死亡形式。这条途径被认为是一种替代的抗癌治疗策略，化学试剂 erastin 通过阻断系统 Xc 诱导铁死亡，导致半胱氨酸缺乏，耗尽细胞内 GSH。线粒体 NADP 依赖性异柠檬酸脱氢酶（IDH2）是产生 NADPH 的主要酶，NADPH 是线粒体 GSH 周转的关键来源。因此，我们假设下调 IDH2 会对 erastin 诱导的铁死亡产生协同作用。在这里，我们研究了 IDH2 敲低对体外培养的人 HT1080 纤维肉瘤和鼠 Hepa1-6 肝癌细胞以及在裸鼠异体 Hepa1-6 细胞移植模型中对铁死亡的影响。我们的结果表明，当 IDH2 下调时，对铁死亡的敏感性大大增加。这项研究支持 IDH2 对铁死亡细胞死亡具有保护作用，并且可以针对该酶使癌细胞对铁死亡敏感。
