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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.
AuthorsYoshihiko Okamoto, Tsuyako Ohkubo, Tetsuro Ikebe, Jun Yamazaki
JournalInternational journal of oncology (Int J Oncol) Vol. 40 Issue 5 Pg. 1431-40 (May 2012) ISSN: 1791-2423 [Electronic] Greece
PMID22267123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anilides
  • Antineoplastic Agents
  • N-(4-methoxyphenyl)-4-menthone-3-carboxamide
  • Pyrimidinones
  • RNA, Messenger
  • TRPM Cation Channels
  • TRPM8 protein, human
  • Menthol
  • icilin
  • Matrix Metalloproteinase 9
Topics
  • Anilides (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Calcium Signaling (drug effects)
  • Carcinoma, Squamous Cell (genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Humans
  • Immunohistochemistry
  • Matrix Metalloproteinase 9 (metabolism)
  • Membrane Potentials
  • Menthol (analogs & derivatives, pharmacology)
  • Neoplasm Invasiveness
  • Patch-Clamp Techniques
  • Pyrimidinones (pharmacology)
  • RNA, Messenger (metabolism)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • TRPM Cation Channels (antagonists & inhibitors, genetics, metabolism)
  • Tongue Neoplasms (genetics, metabolism, pathology)

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