Simvastatin stimulates apoptosis in cholangiocarcinoma by inhibition of Rac1 activity

Abstract Background Simvastatin is a cholesterol-lowering drug that is widely used to prevent and treat atherosclerotic cardiovascular disease. Simvastatin exhibits numerous pleiotropic effects including anti-cancer activity. However, the effect of simvastatin on cholangiocarcinoma has not been eval...

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Bibliographic Details
Published in:Digestive and liver disease 2011-05, Vol.43 (5), p.395-403
Main Authors: Miller, Timothy, Yang, Fuquan, Wise, Candace E, Meng, Fanyin, Priester, Sally, Munshi, Md Kamruzzaman, Guerrier, Micheleine, Dostal, David E, Glaser, Shannon S
Format: Article
Language:English
Subjects:
Anticholesteremic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Bile Duct Neoplasms - metabolism
Bile Duct Neoplasms - pathology
Bile Ducts, Intrahepatic - metabolism
Bile Ducts, Intrahepatic - pathology
Cell Line, Tumor
Cell Survival - drug effects
Cholangiocarcinoma
Cholangiocarcinoma - metabolism
Cholangiocarcinoma - pathology
Epithelial Cells - drug effects
Gastroenterology and Hepatology
Humans
Rac1
rac1 GTP-Binding Protein - drug effects
rac1 GTP-Binding Protein - metabolism
Signal Transduction - drug effects
Simvastatin
Simvastatin - pharmacology
Statistics, Nonparametric
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Summary:Abstract Background Simvastatin is a cholesterol-lowering drug that is widely used to prevent and treat atherosclerotic cardiovascular disease. Simvastatin exhibits numerous pleiotropic effects including anti-cancer activity. However, the effect of simvastatin on cholangiocarcinoma has not been evaluated. Aim The aim of our study was to determine the effect of simvastatin on cholangiocarcinoma proliferation. Methods The effect of simvastatin was evaluated in five human cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, TFK-1, SG231, and HuCCT1) and normal cholangiocyte cell line (HiBEpiC). Results We found that simvastatin stimulates a reduction in cell viability and apoptosis of cholangiocarcinoma cell lines, whilst in normal human cholangiocytes, HiBEpiC, simvastatin inhibits proliferation with no effect on apoptosis. Simvastatin-induced reduction of cell viability was partially blocked by pre-treatment with metabolites of the mevalonate pathway. In Mz-ChA-1 cells, pre-treatment with cholesterol alone stimulated an increase in the number of viable cells and fully restored cell viability following simvastatin treatment. Treatment with simvastatin triggered the loss of lipid raft localised Rac1 and reduction of Rac1 activity in Mz-ChA-1 cells. This effect was prevented by pre-treatment with cholesterol. Conclusion Collectively, our results demonstrate that simvastatin induces cholangiocarcinoma cancer cell death by disrupting Rac1/lipid raft colocalisation and depression of Rac1 activity.
ISSN:1590-8658
1878-3562
DOI:10.1016/j.dld.2011.01.010