Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
复制标题
p62-Keap1-NRF2 通路的激活可防止肝细胞癌细胞中的铁死亡。
DOI：
10.1002/hep.28251
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Sun X;Ou Z;Chen R;Niu X;Chen D;Kang R;Tang D
铁凋亡是最近认识到的一种由铁依赖性脂质活性氧簇积累引起的调节性细胞死亡形式。然而，调节铁凋亡的分子机制仍不清楚。在这里，我们报告，核因子红细胞2相关因子（NRF 2）在保护肝细胞癌（HCC）细胞对铁凋亡的核心作用。在暴露于亚铁盐中毒诱导化合物（例如，erastin、索拉非尼和丁噻鲁胺亚砜亚胺），p62表达阻止了NRF 2降解，并通过Kelch样ECH相关蛋白1的失活增强了随后的NRF 2核积累。此外，核NRF 2与转录辅激活因子小v-maf禽肌肉腱膜纤维肉瘤癌基因同源物（Maf）蛋白（如MafG）相互作用，然后激活醌氧化还原酶1（NQO 1）、血红素加氧酶1（HO 1）和铁蛋白重链1（FTH 1）的转录。在肝癌细胞中通过RNAi敲低p62、NQO 1、HO 1和FTH 1促进erastin和索拉非尼引起的铁凋亡。此外，HCC细胞中NRF 2表达/活性的遗传或药理学抑制增加了erastin和索拉非尼在体外和肿瘤异种移植模型中的抗癌活性。这些发现表明新的分子机制和信号通路的铁凋亡。NRF 2的状态是决定HCC细胞对铁凋亡靶向疗法的治疗反应的关键因素。
Ferroptosis is a recently-recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with the transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (Maf) proteins such as MafG and then activated transcription of quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO1), and ferritin heavy chain 1 (FTH1). Knockdown of p62, NQO1, HO1, and FTH1 by RNAi in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis. The status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in HCC cells.