t-BuOOH induces ferroptosis in human and murine cell lines
t-BuOOH induces ferroptosis in human and murine cell lines
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DOI：
10.1007/s00204-017-2066-y
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发表时间：
2017-10
影响因子：
6.1
通讯作者：
Christine Wenz;D. Faust;Berenike Linz;Christian Turmann;T. Nikolova;J. Bertin;P. Gough;P. Wipf
中科院分区：
文献类型：
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作者：
Christine Wenz;D. Faust;Berenike Linz;Christian Turmann;T. Nikolova;J. Bertin;P. Gough;P. Wipf
活性氧（ROS）诱导的细胞凋亡已被广泛研究。越来越多的证据表明，例如，由过氧化氢 (H2O2) 诱导的 ROS 也可能触发受调节的坏死细胞死亡途径。关于叔丁基过氧化氢（t-BuOOH）（一种广泛使用的氧化应激诱导剂）触发的细胞死亡途径几乎一无所知。 t-BuOOH 诱导的脂质过氧化产物参与许多疾病的病理生理学，例如癌症、心血管疾病或糖尿病。在这项研究中，我们将小鼠成纤维细胞 (NIH3T3) 或人角质形成细胞 (HaCaT) 暴露于 tot-BuOOH（分别为 50 或 200 μM），这会诱导细胞快速坏死。成熟的细胞死亡调节因子，即 p53、聚 (ADP) 核糖聚合酶 1 (PARP-1)、应激激酶 p38 和 c-Jun N 末端激酶 1/2 (JNK1/2) 或受体相互作用丝氨酸/苏氨酸蛋白激酶 1 (RIPK1) 和 3 (RIPK3)，不需要 Fort-BuOOH 介导的细胞死亡。使用选择性抑制剂 Ferrostatin-1 (1 µM) 和 liproxstatin-1 (1 µM)，我们确定了铁死亡（一种最近发现的依赖于铁和脂质过氧化的细胞死亡机制）作为主要的细胞死亡途径。因此，暴露于t-BuOOH会导致对ferrostatin-1和liproxstatin-1敏感的脂质过氧化和胞质ROS增加。铁死亡的执行独立于其他-BuOOH介导的细胞损伤，即线粒体膜电位丧失、DNA双链断裂或复制阻断。 H2O2 在等毒性浓度 (300 μM) 下不会引起铁死亡，并诱导 (1) 较低和 (2) 对铁他汀-1-或利普司他汀-1 不敏感的脂质过氧化增加。我们发现 t-BuOOH 和 H2O2 产生不同的脂质过氧化模式，从而导致不同的细胞死亡途径，并将 t-BuOOH 作为铁死亡的新型诱导剂。
Reactive oxygen species (ROS)-induced apoptosis has been extensively studied. Increasing evidence suggests that ROS, for instance, induced by hydrogen peroxide (H2O2), might also trigger regulated necrotic cell death pathways. Almost nothing is known about the cell death pathways triggered bytertiary-butyl hydroperoxide (t-BuOOH), a widely used inducer of oxidative stress. The lipid peroxidation products induced byt-BuOOH are involved in the pathophysiology of many diseases, such as cancer, cardiovascular diseases, or diabetes. In this study, we exposed murine fibroblasts (NIH3T3) or human keratinocytes (HaCaT) tot-BuOOH (50 or 200 μM, respectively) which induced a rapid necrotic cell death. Well-established regulators of cell death, i.e., p53, poly(ADP)ribose polymerase-1 (PARP-1), the stress kinases p38 and c-Jun N-terminal-kinases 1/2 (JNK1/2), or receptor-interacting serine/threonine protein kinase 1 (RIPK1) and 3 (RIPK3), were not required fort-BuOOH-mediated cell death. Using the selective inhibitors ferrostatin-1 (1 μM) and liproxstatin-1 (1 μM), we identified ferroptosis, a recently discovered cell death mechanism dependent on iron and lipid peroxidation, as the main cell death pathway. Accordingly,t-BuOOH exposure resulted in a ferrostatin-1- and liproxstatin-1-sensitive increase in lipid peroxidation and cytosolic ROS. Ferroptosis was executed independently from othert-BuOOH-mediated cellular damages, i.e., loss of mitochondrial membrane potential, DNA double-strand breaks, or replication block. H2O2did not cause ferroptosis at equitoxic concentrations (300 μM) and induced a (1) lower and (2) ferrostatin-1- or liproxstatin-1-insensitive increase in lipid peroxidation. We identify thatt-BuOOH and H2O2produce a different pattern of lipid peroxidation, thereby leading to different cell death pathways and presentt-BuOOH as a novel inducer of ferroptosis.