Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway

Cancer Lett. 2013 Feb 1;329(1):9-16. doi: 10.1016/j.canlet.2012.08.031. Epub 2012 Sep 7.

Abstract

Simvastatin (SVA) was shown to up-regulate expression of death receptor-5 (DR5), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (pJNK) in human breast cancer cell lines. siRNA knockdown of DR5, CHOP or JNK significantly blocked SVA-induced apoptosis, demonstrating the importance of JNK/CHOP/DR5 signaling pathway in SVA-induced apoptosis. Exogenous addition of either mevalonate or geranylgeranyl pyrophosphate (GGPP) inhibited SVA activation of JNK/CHOP/DR5 pro-apoptotic pathway, indicating that activation of JNK/CHOP/DR5 pro-apoptotic pathway is dependent on SVA inhibition of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase and its intermediate GGPP. Data provide novel insight into better understanding the anticancer mechanisms of SVA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mevalonic Acid / metabolism
  • Polyisoprenyl Phosphates / pharmacology
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Sesquiterpenes / pharmacology
  • Signal Transduction / drug effects
  • Simvastatin / pharmacology*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*

Substances

  • Antineoplastic Agents
  • DDIT3 protein, human
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Polyisoprenyl Phosphates
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Sesquiterpenes
  • Transcription Factor CHOP
  • farnesyl pyrophosphate
  • Simvastatin
  • JNK Mitogen-Activated Protein Kinases
  • geranylgeranyl pyrophosphate
  • Mevalonic Acid