伊利司莫诱导子宫内膜癌细胞发生铜死亡的作用机制  

Mechanism of Elesclomol Induced Cuproptosis in Endometrial Cancer Cells

作　　者：张莎莎[1] 石莹莹 吴春香 葛宁 ZHANG Shasha;SHI Yingying;WU Chunxiang;GE Ning(Department of Pharmacy,Maternal and Child Health Hospital of Hubei Province,Wuhan 430070,China;Department of Oncology,Maternal and Child Health Hospital of Hubei Province,Wuhan 430070,China;School of Public Health,Wuhan University,Wuhan 430071,China)

机构地区：[1]湖北省妇幼保健院药学部,武汉430070 [2]湖北省妇幼保健院肿瘤科,武汉430070 [3]武汉大学公共卫生学院,武汉430071

出　　处：《医药导报》2024年第9期1393-1397,共5页Herald of Medicine

基　　金：湖北省妇幼保健院2021年度面上项目(2021SFYM002)。

摘　　要：目的 探讨铜离子载体伊利司莫诱导子宫内膜癌细胞发生铜死亡的机制。方法 采用不同浓度伊利司莫和氯化铜处理HEC-1-A细胞。细胞计数试剂-8(CCK-8)法检测细胞增殖。酶联免疫吸附测定(ELISA)法检测线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ和Ⅳ。实时荧光定量聚合酶链反应(qRT-PCR)检测mRNA表达。免疫印迹法(Western blotting)和免疫组化法检测蛋白表达。结果 单独加入伊利司莫或氯化铜不影响细胞的存活率,但同时加入50 nmol·L^(-1)伊利司莫和1μmol·L^(-1)铜离子使HEC-1-A细胞存活率明显下降(P<0.01)。伊利司莫诱导的HEC-1-A细胞死亡并不涉及细胞凋亡。采用50 nmol·L^(-1)伊利司莫和1μmol·L^(-1)铜离子处理HEC-1-A细胞后,线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ的水平显著升高。敲减人铁氧还原蛋白1(FDX1)可明显抑制HEC-1-A细胞的铜死亡(P<0.01)。此外,FDX1在子宫内膜癌组织中低表达。结论 伊利司莫可能通过FDX1/线粒体呼吸途径促进子宫内膜癌细胞发生铜死亡。Objective To investigate the mechanism of copper ionophore elesclomol induced cuproptosis in endometrial cancer cells.Methods HEC-1-A cells were treated with different concentrations of copper ion carrier elesclomol and copper chloride.Cell proliferation was detected using a cell counting kit(CCK-8)assay.Enzyme-linked immunosorbent assay(ELISA)detected mitochondrial respiratory chain complexesⅠ,Ⅱ,Ⅲ,and IV.Quantitative real-time polymerase chain reaction(qRT-PCR)was used to detect mRNA expression.Western blotting and immunohistochemistry were used to detect protein expression.Results Adding elesclomol or copper chloride alone to HEC-1-A cells did not affect cell survival.However,the simultaneous addition of 50 nmol·L^(-1) elesclomol and 1μmol·L^(-1) copper ions caused a significant decrease in cell survival(P<0.01).Elesclomol-induced HEC-1-A cell death does not involve the apoptosis mechanism.After treatment with 50 nmol·L^(-1) elesclomol and 1μmol·L^(-1) copper ions in HEC-1-A cells,the levels of mitochondrial respiratory chain complexesⅠ,Ⅱ,andⅢsignificantly increased.After knocking down ferredoxin 1(FDX1),the cuproptosis in HEC-1-A cells was significantly inhibited(P<0.01).In addition,FDX1 was under-expressed in endometrial cancer tissues.Conclusion Elesclomol may promote cuproptosis in endometrial cancer cells through the FDX1/mitochondrial respiratory pathway.

关 键 词：伊利司莫 子宫内膜癌 铜死亡 线粒体呼吸 铁氧还原蛋白1 

分 类 号：R979.1[医药卫生—药品] R737.33[医药卫生—药学]