Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells

Menthol, a naturally occurring compound from peppermint oil, binds and activates the TRPM8 Ca2+-permeable channel that exhibits abnormal expression patterns in prostate cancer, suggesting that TRPM8 links Ca2+ transport pathways to tumor biology. We thus investigated the cellular responses of prostate cancer cells to menthol. Here we found that menthol increases [Ca2+]i via Ca2+ influx mechanism(s) independent of TRPM8 in PC-3 cells. We demonstrated that menthol induces cell death at supramillimolar concentrations in PC-3 cells and the cell death is not suppressed by low extracellular Ca2+ condition which indicates that menthol-induced cell death is not associated with Ca2+ influx pathways. In addition, we showed that menthol increases a phosphorylated form of c-jun N-terminal kinase (JNK) in PC-3 cells through TRPM8-independent mechanisms. Thus, our data indicate that there is an apparent lack of causality between TRPM8 activation and menthol-induced cell death and that menthol can regulate TRPM8-independent Ca2+-transport and cellular processes.