Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current
Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current
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他莫昔芬通过阻断肿胀激活的氯电流抑制雌激素受体阴性肝细胞癌细胞的迁移
DOI：
10.1002/jcp.24245
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发表时间：
2013-05-01
影响因子：
5.6
通讯作者：
Chen, Lixin
中科院分区：
文献类型：
--
作者：
Mao, Jianwen;Yuan, Jian;Chen, Lixin
他莫昔芬是一种三苯乙烯类非甾体抗雌激素抗癌药。它还显示出对雌激素受体（EsR）非依赖性肿瘤转移的抑制作用，但其潜在机制尚不清楚。本研究表明，在ESR阴性和高转移性人肝细胞癌MHCC 97 H细胞中，他莫昔芬以浓度依赖性方式抑制细胞迁移、体积激活的Cl-电流（ICl，vol）和调节性体积减少（RVD），IC 50相似。对细胞迁移率、ICl、vol和RVD的相关性分析表明，细胞迁移率与ICl、vol和RVD呈正相关。通过ClC-3 shRNA或siRNA敲低ClC-3 Cl-通道蛋白的表达抑制了ICl、vol和细胞迁移，并且这些抑制作用不能通过在培养基中添加他莫昔芬进一步增加。结果表明，敲低ClC-3表达可能会耗尽他莫昔芬的影响，他莫昔芬可能会抑制细胞迁移，通过调节ICI，体积和细胞体积。此外，他莫昔芬降低蛋白激酶C（PKC）的活性，这种作用可被PKC激活剂PMA逆转。PMA激活PKC可竞争性下调三苯氧胺对ICl，vol的抑制作用，PMA促进细胞迁移，而ClC-3 siRNA敲低ClC-3表达可消除PMA对细胞迁移的抑制作用。结果表明，他莫昔芬可能通过抑制PKC激活来抑制ICl，vol; ICl，vol可能是他莫昔芬在对癌症，特别是对ESR阴性癌症的抗转移作用中的ESR非依赖性靶点。这一发现可能对他莫昔芬在治疗ESR阳性和ESR阴性癌症的临床应用有意义。J.细胞。生理学（C）2012 Wiley Periodicals，Inc.
Tamoxifen is a triphenylethylene non-steroidal antiestrogen anticancer agent. It also shows inhibitory effects on metastasis of estrogen receptor (EsR)-independent tumors, but the underlying mechanism is unclear. It was demonstrated in this study that, in EsR-negative and highly metastatic human hepatocellular carcinoma MHCC97H cells, tamoxifen-inhibited cell migration, volume-activated Cl- currents (ICl,vol) and regulatory volume decrease (RVD) in a concentration-dependent manner with a similar IC50. Analysis of the relationships between migration, ICl,vol and RVD showed that cell migration was positively correlated with ICl,vol and RVD. Knockdown of the expression of ClC-3 Cl- channel proteins by ClC-3 shRNA or siRNA inhibited ICl,vol, and cell migration, and these inhibitory effects could not be increased further by addition of tamoxifen in the medium. The results suggest that knockdown of ClC-3 expression may deplete the effects of tamoxifen; tamoxifen may inhibit cell migration by modulating ICl,vol and cell volume. Moreover, tamoxifen decreased the activity of protein kinase C (PKC) and the effects were reversed by the PKC activator PMA. Activation of PKC by PMA could competitively downregulate the inhibitory effects of tamoxifen on ICl,vol. PMA promoted cell migration, and knockdown of ClC-3 expression by ClC-3 siRNA abolished the PMA effect on cell migration. The results suggest that tamoxifen may inhibit ICl,vol by suppressing PKC activation; ICl,vol may be an EsR-independent target for tamoxifen in the anti-metastatic action on cancers, especially on EsR-negative cancers. The finding may have an implication in the clinical use of tamoxifen in the treatments of both EsR-positive and EsR-negative cancers. J. Cell. Physiol. (C) 2012 Wiley Periodicals, Inc.