Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1
Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1
复制标题
来曲唑通过下调 FEN1 提高过表达芳香酶的乳腺癌细胞对顺铂的敏感性
DOI：
10.1007/s12094-018-02019-1
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Chen, B.
中科院分区：
文献类型：
--
作者：
Wang, Y.;Li, S.;Chen, B.
目的Flap内切核酸酶1（FEN 1）受雌激素（17 β-雌二醇，E2）的上调，并与人乳腺癌细胞顺铂耐药有关。来曲唑是一种芳香化酶抑制剂，可抑制睾酮转化为雌激素，常用于治疗乳腺癌。然而，来曲唑对芳香化酶过表达的乳腺癌细胞中FEN 1表达和顺铂敏感性的影响尚未见报道。分别通过CCK-8和流式细胞术分析来探索顺铂敏感性。将FEN 1 siRNA和FEN 1表达质粒转染到细胞中以下调或上调FEN 1表达。荧光素酶报告基因检测FEN 1启动子活性。来曲唑下调FEN 1表达，增加顺铂敏感性。来曲唑对顺铂的增敏作用依赖于FEN 1的下调。FEN 1过表达可阻断来曲唑对顺铂的增敏作用。替诺明可上调FEN 1的启动子活性、蛋白表达和ERK/Elk-1的磷酸化水平，且可被来曲唑和MEK 1/2抑制剂U 0126消除。来曲唑下调FEN 1的表达在ERK/Elk-1-dependent manner.ConclusionsOur findings清楚地表明，来曲唑提高顺铂敏感性的乳腺癌细胞过度表达芳香化酶通过下调FEN 1，并建议联合使用来曲唑和顺铂可能是一个潜在的治疗方案，用于缓解顺铂耐药的人乳腺癌。
PurposeFlap endonuclease 1 (FEN1) is up-regulated by estrogen (17 beta-estradiol, E2) and related to cisplatin resistance of human breast cancer cells. Letrozole, an aromatase inhibitor, suppresses the change of testosterone into estrogen and is frequently used to treat breast cancer. However, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase have not been revealed.MethodsThe expression of FEN1 and the proteins in ERK/Elk-1 signaling were evaluated by RT-PCR and Western blot. Cisplatin sensitivity was explored through CCK-8 and flow cytometry analysis, respectively. FEN1 siRNAs and FEN1 expression plasmid were transfected into cells to down-regulate or up-regulate FEN1 expression. The promotor activity of FEN1 was detected using luciferase reporter assay.ResultsFEN1 down-regulation improved cisplatin sensitivity of breast cancer cells overexpressing aromatase. Letrozole down-regulated FEN1 expression and increased cisplatin sensitivity. The sensitizing effect of letrozole to cisplatin was dependent on FEN1 down-regulation. FEN1 overexpression could block the sensitizing effect of letrozole to cisplatin. Testosterone up-regulated the promotor activity, protein expression of FEN1, and phosphorylation of ERK/Elk-1, which could be eliminated by both letrozole and MEK1/2 inhibitor U0126. Letrozole down-regulated FEN1 expression in an ERK/Elk-1-dependent manner.ConclusionsOur findings clearly demonstrate that letrozole improves cisplatin sensitivity of breast cancer cells overexpressing aromatase via down-regulation of FEN1 and suggest that a combined use of letrozole and cisplatin may be a potential treatment protocol for relieving cisplatin resistance in human breast cancer.