title: Simvastatin induced HCT116 colorectal cancer cell apoptosis through p38MAPK-p53-survivin signaling cascade.
abstract: BACKGROUND
  Statins, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with cholesterol-lowering properties, were recently shown to exhibit anti-cancer effects. However, the molecular mechanism underlying statin-induced cancer cell death remains to be elucidated. Elevated level of survivin is often found over-expressed in human cancers and has been implicated in the progression of tumorigenesis. Given its central role in cell division and action as an apoptosis suppressor, survivin represents a potential molecular target in cancer management.
  
  
  METHODS
  In this study, we explored the underlying mechanisms in simvastatin-induced HCT116 colorectal cancer cell apoptosis.
  
  
  RESULTS
  Simvastatin decreased cell viability and induced cell apoptosis in HCT116 cells. These results are associated with the modulation of p21(cip/Waf1) and survivin. Survivin knockdown using survivin siRNAs also decreased cell viability and induced cell apoptosis. Simvastatin's actions on p21(cip/Waf1), survivin and apoptosis were reduced in p53 null HCT116 cells. Simvastatin caused an increase in p53 phosphorylation and acetylation. In addition, simvastatin activated p38 mitogen-activated protein kinase (p38MAPK), whereas an inhibitor of p38MAPK signaling abrogated simvastatin's effects of increasing p53 and p21(cip/Waf1) promoter luciferase activity. Cell viability and survivin promoter luciferase activity in the presence of simvastatin were also restored by p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p53 and p63 binding to the promoter region increased after simvastatin exposure.
  
  
  CONCLUSIONS
  Simvastatin activates the p38MAPK-p53-survivin cascade to cause HCT116 colorectal cancer cell apoptosis.
  
  
  CONCLUSIONS
  This study delineates, in part, the underlying mechanisms of simvastatin in decreasing survivin and subsequent colorectal cancer cell apoptosis.
authors.affiliation: Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
authors.forename: Hang-Lung
authors.initials: HL
authors.lastname: Chang
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Kuo
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.forename: Pei-Ting
authors.initials: PT
authors.lastname: Chiu
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Huang
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C107489:BIRC5 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases