基因敲除
癌症研究
KEAP1型
转录因子
肝细胞癌
索拉非尼
血红素加氧酶
化学
铁蛋白
血红素
细胞凋亡
细胞生物学
生物
生物化学
基因
酶
作者
Xiaofang Sun,Zhanhui Ou,Ruochan Chen,Xiaohua Niu,De Chen,Rui Kang,Daolin Tang
出处
期刊:Hepatology
[Wiley]
日期:2015-11-26
卷期号:63 (1): 173-184
被引量:1252
摘要
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 2 (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 transcriptional coactivator small v‐maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1. Knockdown of p62, quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1 by RNA interference 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. Conclusion: 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. (H epatology 2016;63:173–184)
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