Simvastatin induced HCT116 colorectal cancer cell apoptosis through p38MAPK-p53-survivin signaling cascade

Hang Lung Chang, Chih Yu Chen, Ya Fen Hsu, Wen Shin Kuo, George Ou, Pei Ting Chiu, Yu Han Huang, Ming Jen Hsu

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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 p21cip/Waf1 and survivin. Survivin knockdown using survivin siRNAs also decreased cell viability and induced cell apoptosis. Simvastatin's actions on p21cip/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 p21cip/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. General significance This study delineates, in part, the underlying mechanisms of simvastatin in decreasing survivin and subsequent colorectal cancer cell apoptosis.

Original languageEnglish
Pages (from-to)4053-4064
Number of pages12
JournalBiochimica et Biophysica Acta - General Subjects
Volume1830
Issue number8
DOIs
Publication statusPublished - 2013

Keywords

  • Apoptosis
  • Colorectal cancer
  • p38MAPK
  • p53
  • Simvastatin
  • Survivin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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