The sensitivity of head and neck carcinoma cells to statins is related to the expression of their Ras expression status, and statin-induced apoptosis is mediated via suppression of the Ras/ERK and Ras/mTOR pathways

Clin Exp Pharmacol Physiol. 2017 Feb;44(2):222-234. doi: 10.1111/1440-1681.12690.

Abstract

Statins induce apoptosis of tumour cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanisms remain poorly understood. The present study showed that the induction of apoptosis by statins in four different human head and neck squamous cell carcinoma (HNSCC) cell lines, HSC-3, HEp-2, Ca9-22, and SAS cells was mediated by increased caspase-3 activity. Statins induced apoptosis by the suppression of geranylgeranyl pyrophosphate biosynthesis. Furthermore, statins decreased the levels of phosphorylated ERK and mTOR by inhibiting the membrane localization of Ras and enhancing Bim expression in HSC-3 and HEp-2 cells. We also found that in all the cell types analyzed, the IC50 values for fluvastatin and simvastatin were highest in HEp-2 cells. In addition, HSC-3, Ca9-22, and SAS cells had higher Ras expression and membrane localization, higher activation of ERK1/2 and mTOR, and lower levels of Bim expression than HEp-2 cells. Our results indicate that statins induce apoptosis by increasing the activation of caspase-3 and by enhancing Bim expression through inhibition of the Ras/ERK and Ras/mTOR pathways. Furthermore, the sensitivity of HNSCC cells to statin treatment was closely related to Ras expression and prenylation levels, indicating that statins may act more effectively against tumours with high Ras expression and Ras-variability. Therefore, our findings support the use of statins as potential anticancer agents.

Keywords: Bim; Ras; extracellular signal regulated-protein kinase ½; mammalian target of rapamycin; statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Bcl-2-Like Protein 11 / genetics
  • Bcl-2-Like Protein 11 / metabolism*
  • Caspase 3 / metabolism
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Head and Neck Neoplasms* / metabolism
  • Head and Neck Neoplasms* / pathology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Bcl-2-Like Protein 11
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Caspase 3
  • ras Proteins