Document Detail


Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current.
MedLine Citation:
PMID:  23042559     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 (I(cl,vol) ) and regulatory volume decrease (RVD) in a concentration-dependent manner with a similar IC(50) . Analysis of the relationships between migration, I(cl,vol) and RVD showed that cell migration was positively correlated with I(cl,vol) and RVD. Knockdown of the expression of ClC-3 Cl(-) channel proteins by ClC-3 shRNA or siRNA inhibited I(cl,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 I(cl,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 I(Cl,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 I(Cl,vol) by suppressing PKC activation; I(cl,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. © 2012 Wiley Periodicals, Inc.
Authors:
Jianwen Mao; Jian Yuan; Liwei Wang; Haifeng Zhang; Xiaobao Jin; Jiayong Zhu; Hongzhi Li; Bin Xu; Lixin Chen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-5
Journal Detail:
Title:  Journal of cellular physiology     Volume:  -     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Pharmacology and Department of Physiology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Key Laboratory for Bioactive Drugs Research and Department of Biology, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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