Estrogen-dependent disruption of intracellular iron metabolism augments the cytotoxic effects of doxorubicin in select breast and ovarian cancer cells
Estrogen-dependent disruption of intracellular iron metabolism augments the cytotoxic effects of doxorubicin in select breast and ovarian cancer cells
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DOI：
10.2147/cmar.s204852
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Hamad, Mawieh
中科院分区：
文献类型：
--
作者：
Bajbouj, Khuloud;Shafarin, Jasmin;Hamad, Mawieh
简介：癌细胞中铁含量的增加与对化疗的抵抗有关。最近的研究表明，雌激素（E-2）抑制hepcidin的合成和增强细胞内铁流出。在此，我们研究了E-2驱动的细胞内铁流出是否使癌细胞对阿霉素（Dox）诱导的细胞毒性更敏感。方法：用E-2、Dox或两者联合处理的乳腺癌、卵巢癌和肝癌细胞系评估细胞内铁状态、线粒体功能、细胞周期和凋亡。与Dox处理的细胞相比，E-2+Dox处理的MCF 7、SKOV 3和MDA-MB 231细胞的凋亡增加。E-2+ Dox处理的细胞中γ H2 AX的表达显著高于Dox处理的细胞，而Survivin的表达显著低于Dox处理的细胞。在48小时，E-2+Dox诱导了sub-G（1）凋亡细胞百分比的显著增加，CHK 1表达增加，细胞周期蛋白D1、CDK 4和CDK 6表达降低。E-2+ Dox处理的细胞铁转运蛋白和铁蛋白的表达显著高于Dox处理的细胞，而TfR 1的表达显著低于Dox处理的细胞。在E2 + Dox处理的细胞中，在处理后48小时，细胞内铁含量显著降低。最后，E-2+ Dox处理的细胞表现出更高水平的线粒体膜超极化比Dox处理cells.Conclusion：这些研究结果表明，E-2破坏细胞内铁代谢的方式，增加细胞对Dox诱导的细胞毒性的敏感性。
Introduction: Increased iron content in cancer cells is associated with resistance to chemotherapy. Recent studies have demonstrated that estrogen (E-2) suppresses hepcidin synthesis and enhances intracellular iron efflux. Herein, we investigated whether E-2-driven intracellular iron efflux renders cancer cells more susceptible to doxorubicin (Dox)-induced cytotoxicity.Methods: Breast, ovarian, and liver cancer cell lines treated with E-2, Dox, or a combination of both were assessed for intracellular iron status, mitochondrial function, cell cycle, and apoptosis.Results: E-2+Dox treatment in MCF7, SKOV3 and MDA-MB231 cells resulted in enhanced apoptosis compared with Dox-treated cells. Expression of gamma H2AX was significantly higher and that of survivin significantly lower in E-2+Dox-treated cells than Dox-treated cells. At 48 hours, E-2+Dox had induced a significant increase in the percentage of sub-G(1) apoptotic cells, increased CHK1 expression, and decreased cyclin D1, CDK4, and CDK6 expression. Ferroportin and ferritin expression was significantly higher and that of TfR1 significantly lower in E-2+Dox-treated cells than Dox-treated cells. Intracellular iron content was significantly reduced in E-2+Dox-treated cells at 48 hours posttreatment. Lastly, E-2+Dox-treated cells showed higher levels of mitochondrial membrane hyperpolarization than Dox-treated cells.Conclusion: These findings suggest that E-2 disrupts intracellular iron metabolism in such a way that increases cell susceptibility to Dox-induced cytotoxicity.