Activation of ClC-3 chloride channel by 17-estradiol relies on the estrogen receptor expression in breast cancer
Activation of ClC-3 chloride channel by 17-estradiol relies on the estrogen receptor expression in breast cancer
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17β-雌二醇对 ClC-3 氯离子通道的激活依赖于乳腺癌中雌激素受体 α 的表达
DOI：
10.1002/jcp.25963
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发表时间：
2018-02-01
影响因子：
5.6
通讯作者：
Zhu, Linyan
中科院分区：
文献类型：
--
作者：
Yang, Haifeng;Ma, Lianshun;Zhu, Linyan
尽管被广泛研究，但雌激素促进乳腺癌生长的机制仍未完全阐明。他莫昔芬是一种治疗ER+乳腺癌的抗雌激素药物，也是一种高亲和力的氯离子通道阻滞剂。在这项研究中，我们探讨了氯通道参与雌激素在乳腺癌中的作用。我们发现17-雌二醇(17-E_2)浓度依赖地激活ER+乳腺癌MCF-7细胞的氯电流。细胞外高渗刺激和氯通道阻滞剂NPPB和DIDS可抑制17-E_2激活的氯电流。降低ClC-3蛋白表达导致17-E_2激活的氯电流耗竭。17-E_2激活的氯电流依赖于ER的表达。首先，在ER乳腺癌MDA-MB-231细胞中未观察到17-E_2激活的氯电流。其次，ER拮抗剂他莫昔芬和ICI182,780以及ER表达的下调可抑制或取消17-E_2激活的氯电流。第三，ESR1基因转染可诱导MDA-MB-231细胞ER表达，并可观察到17-E_2激活的氯电流。在MCF-7细胞中，17-E_2处理后ER和ClC-3主要定位于胞核，移位到细胞膜和胞浆。下调ER表达可降低CLC-3蛋白的表达。相反，下调ClC-3的表达并不影响ER的表达。综上所述，我们的研究结果表明ClC-3是17-E2的潜在靶点，并受乳腺癌细胞中ER的调控。ClC-3的药理调节可能为乳腺癌患者的抗雌激素治疗提供更深层次的理解。
Although extensively studied, the mechanisms by which estrogen promotes breast cancer growth remain to be fully elucidated. Tamoxifen, an antiestrogen agent to treat ER+ breast cancer, is also a high-affinity blocker of the chloride channels. In this study, we explored the involvement of the chloride channels in the action of estrogen in breast cancer. We found that 17-estradiol (17-E2) concentration-dependently activated the chloride currents in ER+ breast cancer MCF-7 cells. Extracellular hypertonic challenge and chloride channel blockers, NPPB and DIDS inhibited the 17-E2-activated chloride currents. Decreased the ClC-3 protein expression caused the depletion of the 17-E2-activated chloride currents. 17-E2-activated chloride currents which relied on the ER expression were demonstrated by the following evidences. Firstly, 17-E2-activated chloride currents could not be observed in ER- breast cancer MDA-MB-231 cells. Secondly, ER antagonists, tamoxifen and ICI 182,780, and downregulation of ER expression inhibited or abolished the 17-E2-activated chloride currents. Thirdly, ER expression was induced in MDA-MB-231 cells by ESR1 gene transfection, and then 17-E2-activated chloride currents could be observed. In MCF-7 cells, ER and ClC-3 mainly located in nucleus and translocated to cell plasma and membrane with respect to co-localization following treatment of 17-E2. Downregulation of ER expression could decrease the expression of ClC-3 protein. Conversely, downregulation of ClC-3 expression did not influence the ER expression. Taken together, our findings demonstrated that ClC-3 is a potential target of 17-E2 and is modulated by the ER in breast cancer cell. Pharmacological modulation of ClC-3 may provide a deep understanding in antiestrogen treatment of breast cancer patients.