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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
Author(s) -
Tsubaki Masanobu,
Fujiwara Daichiro,
Takeda Tomoya,
Kino Toshiki,
Tomonari Yoshika,
Itoh Tatsuki,
Imano Motohiro,
Satou Takao,
Sakaguchi Katsuhiko,
Nishida Shozo
Publication year - 2017
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12690
Subject(s) - apoptosis , statin , prenylation , pi3k/akt/mtor pathway , mapk/erk pathway , cancer research , simvastatin , fluvastatin , head and neck squamous cell carcinoma , cell culture , geranylgeranyl pyrophosphate , chemistry , microbiology and biotechnology , signal transduction , biology , medicine , pharmacology , cancer , biochemistry , head and neck cancer , genetics , enzyme
Summary 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, HE p‐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 HE p‐2 cells. We also found that in all the cell types analyzed, the IC 50 values for fluvastatin and simvastatin were highest in HE p‐2 cells. In addition, HSC ‐3, Ca9‐22, and SAS cells had higher Ras expression and membrane localization, higher activation of ERK 1/2 and mTOR , and lower levels of Bim expression than HE p‐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.