Identification of PRDX6 as a regulator of ferroptosis  

作　　者：Bin Lu Xiao-bing Chen Yu-cai Hong Hong Zhu Qiao-jun He Bo Yang Mei-dan Ying Ji Cao 

机构地区：[1]Institute of Pharmacology and Toxicology,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [2]Department of Emergency Medicine,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China

出　　处：《Acta Pharmacologica Sinica》2019年第10期1334-1342,共9页中国药理学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(No.81872885 to Ji Cao;No.81625024 to Bo Yang);the Department of Education of Zhejiang Province(Y201430401 to Ji Cao);the Talent Project of Zhejiang Association for Science and Technology(No.2018YCGC002 to Ji Cao);the Project of Zhejiang Medical Science and Technology(2015KYA141 to Yu-cai Hong).

摘　　要：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.

关 键 词：PRDX6 ferroptosis iPLA2 ACTIVITY HEME oxygenase-1 ANTITUMOR THERAPY 

分 类 号：R73[医药卫生—肿瘤]