Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Acta Pharmacol Sin. 2019 Oct;40(10):1334-1342. doi: 10.1038/s41401-019-0233-9. Epub 2019 Apr 29.
Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.
铁死亡是一种新发现的铁依赖性非凋亡性细胞死亡形式，由脂质活性氧（LOOH）触发。铁死亡的失调与癌症高度相关，诱导铁死亡也被提出作为癌症治疗的一种潜在策略。尽管已经确定了几个参与铁死亡的关键调节因子，但该过程的分子机制在很大程度上仍不清楚。在这里，我们报告过氧化物酶 6（PRDX6）是铁死亡细胞死亡的真正负调节剂。细胞内 PRDX6 的敲低显着增强了铁死亡诱导剂（Erastin 和 RSL-3）引发的 LOOH 和铁死亡细胞死亡，这与血红素加氧酶-1 的转录激活相关。此外，血红素加氧酶-1 的过表达增强了 Erastin 和 RSL-3 触发的 LOOH，表明血红素加氧酶-1 介导了 PRDX6 沉默增强的铁死亡。更重要的是，特定 PRDX6 磷脂酶 A2（iPLA2）抑制剂 MJ-33 的应用协同增强了 Erastin 诱导的铁死亡，表明 PRDX6 通过其 iPLA2 活性去除 LOOH。因此，我们的研究结果揭示了 PRDX6 在保护细胞免受铁死亡中的重要作用，并提供了一个潜在的靶点，以提高基于铁死亡的化疗的抗肿瘤活性。
