Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells.
Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells.
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半胱氨酸双加氧酶 1 介导人胃癌细胞中 Erastin 诱导的铁死亡
DOI：
10.1016/j.neo.2017.10.005
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Shi M
中科院分区：
文献类型：
--
作者：
Hao S;Yu J;He W;Huang Q;Zhao Y;Liang B;Zhang S;Wen Z;Dong S;Rao J;Liao W;Shi M
背景：铁凋亡是最近发现的一种铁依赖性非凋亡性细胞死亡。其特征在于脂质修复酶谷胱甘肽过氧化物酶4（GPX4）的活性丧失和致死性活性脂质氧的积累。然而，我们对胃癌细胞中的铁凋亡及其分子机制仍知之甚少。在这里，我们证明erastin，一个经典的诱导剂，铁凋亡，诱导这种形式的细胞死亡在GC细胞和半胱氨酸双加氧酶1（CDO1）在这一过程中发挥了重要作用。方法：我们采用实时定量聚合酶链反应、蛋白质印迹、细胞活力测定、活性氧测定、谷胱甘肽测定、脂质过氧化测定、RNA干扰和基因转染、免疫荧光染色、双荧光素酶报告基因测定、透射电镜和染色质免疫沉淀法研究了GC细胞中铁凋亡的调控。采用小鼠异种移植实验研究其体内作用机制。结果：在体外和体内，沉默CDO1抑制erastin诱导的GC细胞铁凋亡。抑制CDO1恢复细胞GSH水平，防止ROS的产生，并减少脂质过氧化的终产物之一丙二醛。此外，沉默COO1维持erastin处理的细胞线粒体形态稳定。从机制上讲，c-Myb转录调节CDO1，抑制CDO1表达上调GPX4表达。结论：我们的研究结果提供了一个更好的理解铁凋亡及其分子机制在GC细胞，深入了解铁凋亡介导的癌症治疗。
BACKGROUND: Ferroptosis is a recently discovered form of iron-dependent nonapoptotic cell death. It is characterized by loss of the activity of the lipid repair enzyme, glutathione peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. However, we still know relatively little about ferroptosis and its molecular mechanism in gastric cancer (GC) cells. Here, we demonstrate that erastin, a classic inducer of ferroptosis, induces this form of cell death in GC cells and that cysteine dioxygenase 1 (CDO1) plays an important role in this process. METHODS: We performed quantitative real-time polymerase chain reaction, Western blotting, cell viability assay, reactive oxygen species (ROS) assay, glutathione assay, lipid peroxidation assay, RNAi and gene transfection, immunofluorescent staining, dual-luciferase reporter assay, transmission electron microscopy, and chromatin immunoprecipitation assay to study the regulation of ferroptosis in GC cells. Mouse xenograft assay was used to figure out the mechanism in vivo. RESULTS: Silencing CDO1 inhibited erastin-induced ferroptosis in GC cells both in vitro and in vivo. Suppression of CDO1 restored cellular GSH levels, prevented ROS generation, and reduced malondialdehyde, one of the end products of lipid peroxidation. In addition, silencing COO1 maintained mitochondrial morphologic stability in erastin-treated cells. Mechanistically, c-Myb transcriptionally regulated CDO1, and inhibition of CDO1 expression upregulated GPX4 expression. CONCLUSIONS: Our findings give a better understanding of ferroptosis and its molecular mechanism in GC cells, gaining insight into ferroptosis-mediated cancer treatment.
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影响因子：
2.1
作者：
Conrad M;Friedmann Angeli JP
通讯作者：
Friedmann Angeli JP
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
影响因子：
11.4
作者：
Booken, N.;Gratchev, A.;Goerdt, S.
通讯作者：
Goerdt, S.
影响因子：
2.3
作者：
Gout, PW;Simms, CR;Robertson, MC
通讯作者：
Robertson, MC
presparlglycine抑制下龙/牛磺酸的合成，并升高原发性小鼠肝细胞中的胱淀粉和同型半胱氨酸的浓度。
影响因子：
3.5
作者：
Jurkowska, Halina;Stipanuk, Martha H.;Hirschberger, Lawrence L.;Roman, Heather B.
通讯作者：
Roman, Heather B.