Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade

Shiu Wen Huang, I. Tsu Chyuan, Ching Shiue, Meng Chieh Yu, Ya Fen Hsu, Ming Jen Hsu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

There is increasing evidence that statins, which are widely used in lowering serum cholesterol and the incidence of cardiovascular diseases, also exhibits anti-tumour properties. The underlying mechanisms by which statins-induced cancer cell death, however, remain incompletely understood. In this study, we explored the anti-tumour mechanisms of a lipophilic statin, lovastatin, in MCF-7 breast cancer cells. Lovastatin inhibited cell proliferation and induced cell apoptosis. Lovastatin caused p21 elevation while reduced cyclin D1 and survivin levels. Lovastatin also increased p53 phosphorylation, acetylation and its reporter activities. Results from chromatin immunoprecipitation analysis showed that p53 binding to the survivin promoter region was increased, while Sp1 binding to the region was decreased, in MCF-7 cells after lovastatin exposure. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation. Lovastatin's enhancing effects on p53 activation, p21 elevation and survivin reduction were significantly reduced in the presence of p38MAPK signalling inhibitor. Furthermore, LKB1-AMPK signalling blockade abrogated lovastatin-induced p38MAPK and p53 phosphorylation. Together these results suggest that lovastatin may activate LKB1-AMPK-p38MAPK-p53-survivin cascade to cause MCF-7 cell death. The present study establishes, at least in part, the signalling cascade by which lovastatin induces breast cancer cell death.

Original languageEnglish
Pages (from-to)1822-1836
Number of pages15
JournalJournal of Cellular and Molecular Medicine
Volume24
Issue number2
DOIs
Publication statusPublished - Jan 1 2020

Keywords

  • breast cancer
  • liver kinase B1
  • lovastatin
  • p53
  • surviving

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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