title: Blockade of TRPM8 activity reduces the invasion potential of oral squamous             carcinoma cell lines.
abstract: Several members of the transient receptor potential (TRP)-channel family             are expressed in cancer cells. One, cold/menthol-sensitive TRPM8, is reportedly             an important player in carcinogenesis in human prostate cancer, although its involvement             in oral squamous cell carcinoma (SCC) remains unclear. The present immunohistochemistry             and RT-PCR results revealed intense TRPM8 expression in two SCC cell lines, HSC3             and HSC4, derived from the human tongue. Menthol, icilin, and a more specific             TRPM8 agonist (WS-12) induced non-specific cation currents, with Ca2+ permeability             being greater than that of Na+ or K+. The novel TRPM8 antagonist RQ-00203078 (RQ)             profoundly reduced such agonist-induced cation currents. Intracellular Ca2+ imaging             revealed that menthol induced both intracellular Ca2+ release and store-operated             Ca2+ entry, with RQ inhibiting each effect. To assess the possible pathophysiological             role of TRPM8 in oral SCC, we performed motility and invasion assays, and gelatin             zymography. Menthol augmented the migration and invasion abilities of both HSC3             and HSC4 cells by potentiating MMP-9 activity. RQ suppressed all of these effects.             These results may aid understanding of the pathophysiological implications of             TRPM8 channels in the oral SCC cells, support TRP proteins as valuable targets             for pharmaceutical intervention, and inform the targeting of oral SCC in which             the prognosis is poor.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Fukuoka Dental                     College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Tsuyako
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikebe
authors.forename: Jun
authors.initials: J
authors.lastname: Yamazaki
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008564:Membrane Potentials; D008610:Menthol / Q000031:analogs & derivatives / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D018408:Patch-Clamp Techniques; D011744:Pyrimidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C533807:N-(4-methoxyphenyl)-4-menthone-3-carboxamide; D011744:Pyrimidinones; D012333:RNA, Messenger; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D008610:Menthol; C490483:icilin; D020780:Matrix Metalloproteinase 9