title: 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 evaluated.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Collectively, our results demonstrate that simvastatin induces cholangiocarcinoma cancer cell death by disrupting Rac1/lipid raft colocalisation and depression of Rac1 activity.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, 702 Southwest HK Dodgen Loop, Temple, TX, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Miller
authors.forename: Fuquan
authors.initials: F
authors.lastname: Yang
authors.forename: Candace E
authors.initials: CE
authors.lastname: Wise
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Sally
authors.initials: S
authors.lastname: Priester
authors.forename: Md Kamruzzaman
authors.initials: MK
authors.lastname: Munshi
authors.forename: Micheleine
authors.initials: M
authors.lastname: Guerrier
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Glaser
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; C107953:RAC1 protein, human; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein