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

Biochim Biophys Acta. 2009 Jan;1792(1):33-8. doi: 10.1016/j.bbadis.2008.09.012. Epub 2008 Oct 9.


Menthol, a naturally occurring compound from peppermint oil, binds and activates the TRPM8 Ca(2+)-permeable channel that exhibits abnormal expression patterns in prostate cancer, suggesting that TRPM8 links Ca(2+) transport pathways to tumor biology. We thus investigated the cellular responses of prostate cancer cells to menthol. Here we found that menthol increases [Ca(2+)](i) via Ca(2+) 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 Ca(2+) condition which indicates that menthol-induced cell death is not associated with Ca(2+) 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 Ca(2+)-transport and cellular processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Tumor
  • Humans
  • Ion Transport / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Menthol / pharmacology*
  • Nerve Tissue Proteins / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Signal Transduction / drug effects
  • TRPA1 Cation Channel
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Transient Receptor Potential Channels / metabolism


  • Calcium Channels
  • Nerve Tissue Proteins
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPM Cation Channels
  • TRPM8 protein, human
  • Transient Receptor Potential Channels
  • Menthol
  • JNK Mitogen-Activated Protein Kinases
  • Calcium