ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron  

作　　者：Shan Lu Xuan-zhong Wang Chuan He Lei Wang Shi-peng Liang Chong-cheng Wang Chen Li Tian-fei Luo Chun-sheng Feng Zhen-chuan Wang Guang-fan Chi Peng-fei Ge 

机构地区：[1]Department of Neurosurgery,First Hospital of Jilin University,Changchun 130021,China [2]Research Center of Neuroscience,First Hospital of Jilin University,Changchun 130021,China [3]Department of Neurology,First Hospital of Jilin University,Changchun 130021,China [4]Department of Anesthesiology,First Hospital of Jilin University,Changchun 130021,China [5]Key Laboratory of Pathobiology,Ministry of Education,Jilin University,Changchun 130021,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1690-1702,共13页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81772669 and 81972346);Changbaishan Scholar Project of Jilin Province(2013026);Scientific Research Foundation of Jilin Province(20190701051GH and 20200201405JC);the Achievement Transformation Fund of the First Hospital of Jilin University(CGZHYD202012-028).

摘　　要：Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H_(2)O_(2) via Fenton reaction,in which the role of activating transcription factor 3(ATF3)remains elusive.Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica,which has shown potent antitumor activity against various tumors,including glioma.In this study,we showed that brucine inhibited glioma cell growth in vitro and in vivo,which was paralleled by nuclear translocation of ATF3,lipid peroxidation,and increases of iron and H_(2)O_(2).Furthermore,brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine(500μM)or improved by ferric ammonium citrate(500μM).Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1(50μM)or liproxstatin-1(30μM)rescued brucine-induced glioma cell death.Moreover,knockdown of ATF3 prevented brucine-induced accumulation of iron and H_(2)O_(2) and glioma cell death.We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress.ATF3 promoted brucine-induced H_(2)O_(2) accumulation via upregulating NOX4 and SOD1 to generate H_(2)O_(2) on one hand,and downregulating catalase and xCT to prevent H_(2)O_(2) degradation on the other hand.H_(2)O_(2) then contributed to brucine-triggered iron increase and transferrin receptor upregulation,as well as lipid peroxidation.This was further verified by treating glioma cells with exogenous H_(2)O_(2) alone.Moreover,H_(2)O_(2) reversely exacerbated brucine-induced ER stress.Taken together,ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H_(2)O_(2) and iron.

关 键 词：GLIOMA BRUCINE ferroptosis ATF3 hydrogen peroxide ER stress NOX4 

分 类 号：R96[医药卫生—药理学] R73[医药卫生—药学]