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 Ca(2+) signaling. Among this subfamily, TRPM8 (also known as Trp-p8) is a Ca(2+)-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 Ca(2+) influx. The application of menthol, an agonist for TRPM8 channel, elevated cytosolic Ca(2+) concentration in a concentration-dependent manner with an EC(50) value of 286 microM in melanoma cells. Menthol-induced responses were significantly abolished by the removal of external Ca(2+). Moreover, inward currents at a holding potential of -60 mV in melanoma cells were markedly potentiated by the addition of 300 microM 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 Ca(2+) handling pathway, providing us with a novel target of drug development for malignant melanoma.
Yamamura
Hisao
H
Dept. of Molecular Morphology, Graduate School of Medical Sciences, Nagoya City Univ., 1 Kawasumi Mizuhocho Mizuhoku, Nagoya 467-8601, Japan. yamamura@med.nagoya-cu.ac.jp
Ugawa
Shinya
S
Ueda
Takashi
T
Morita
Akimichi
A
Shimada
Shoichi
S
D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects; D008610:Menthol / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D008610:Menthol; D002118:Calcium