ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron.
ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron.
复制标题
ATF3 通过促进过氧化氢和铁促进马钱子碱触发的神经胶质瘤细胞铁死亡
DOI：
10.1038/s41401-021-00700-w
复制
发表时间：
2021-10
影响因子：
8.2
通讯作者：
Ge PF
中科院分区：
文献类型：
--
作者：
Lu S;Wang XZ;He C;Wang L;Liang SP;Wang CC;Li C;Luo TF;Feng CS;Wang ZC;Chi GF;Ge PF
亚铁凋亡细胞死亡的特征是亚铁和H2 O2通过芬顿反应引发铁依赖性脂质过氧化反应，其中转录激活因子3（activating transcription factor 3，ATF 3）的作用尚不清楚。马钱子碱是从马钱子种子中提取的一种弱碱性吲哚类生物碱，对包括胶质瘤在内的多种肿瘤具有较强的抗肿瘤活性。在本研究中，我们发现马钱子碱在体外和体内抑制胶质瘤细胞的生长，这是通过ATF 3的核转位，脂质过氧化，铁和H2 O2的增加来解释的。此外，去铁胺（500 μ M）螯合细胞内铁或柠檬酸铁铵（500 μ M）促进细胞内铁时，马钱子碱诱导的脂质过氧化反应被抑制或加剧。用亲脂性抗氧化剂ferrostatin-1（50 μM）或livestatin-1（30 μM）抑制脂质过氧化，挽救了马钱子碱诱导的胶质瘤细胞死亡。此外，ATF 3的敲低阻止了马钱子碱诱导的铁和H2 O2的积累以及胶质瘤细胞的死亡。我们发现，马钱子碱诱导ATF 3上调和易位到细胞核通过激活ER应激。ATF 3一方面通过上调NOX 4和SOD 1产生H2 O2，另一方面通过下调过氧化氢酶和xCT抑制H2 O2降解，从而促进马钱子碱诱导的H2 O2积累。H2 O2则有助于马钱子碱引发的铁增加和转铁蛋白受体上调，以及脂质过氧化。用外源性H2 O2单独处理胶质瘤细胞进一步证实了这一点。此外，H2 O22可加重马钱子碱诱导的内质网应激。综上所述，ATF 3通过增加H2 O2和铁参与马钱子碱诱导的胶质瘤细胞铁凋亡。
Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2via 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 ofStrychnos 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 H2O2. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H2O2accumulation via upregulating NOX4 and SOD1 to generate H2O2on one hand, and downregulating catalase and xCT to prevent H2O2degradation on the other hand. H2O2then 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 H2O2alone. Moreover, H2O2reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2and iron.
登录
查看更多内容
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
ATF3通过上调CYR61表达抑制肝癌细胞的肿瘤发生和进展
DOI：
10.1186/s13046-018-0919-8
发表时间：
2018-10-30
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen C;Ge C;Liu Z;Li L;Zhao F;Tian H;Chen T;Li H;Yao M;Li J
通讯作者：
Li J
影响因子：
5.4
作者：
Ma S;Pang C;Song L;Guo F;Sun H
通讯作者：
Sun H
影响因子：
2.9
作者：
Li Miao;Li Ping;Ma Feng
通讯作者：
Ma Feng
影响因子：
4.6
作者：
Delbrel, Eva;Soumare, Abdoulaye;Boncoeur, Emilie
通讯作者：
Boncoeur, Emilie