TRPM8 activation suppresses cellular viability in human melanoma

The transient receptor potential melastatin subfamily (TRPM), which is a mammalian homologue of cell death-regulated genes in Caenorhabditis elegans and Drosophila, has potential roles in the process of the cell cycle and regulation of Ca2+ signaling. Among this subfamily, TRPM8 (also known as Trp-p8) is a Ca2+-permeable channel that was originally identified as a prostate-specific gene upregulated in tumors. Here we showed that the TRPM8 channel was expressed in human melanoma G-361 cells, and activation of the channel produced sustainable Ca2+ influx. The application of menthol, an agonist for TRPM8 channel, elevated cytosolic Ca2+ concentration in a concentration-dependent manner with an EC50 value of 286 mu M in melanoma cells. Menthol-induced responses were significantly abolished by the removal of external Ca2+. Moreover, inward currents at a holding potential of -60 mV in melanoma cells were markedly potentiated by the addition of 300 mu M menthol. The most striking finding was that the viability of melanoma cells was dose-dependently depressed in the presence of menthol. These results reveal that a functional TRPM8 protein is expressed in human melanoma cells to involve the mechanism underlying tumor progression via the Ca2(+) handling pathway, providing us with a novel target of drug development for malignant melanoma.