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.