Waixenicin A inhibits cell proliferation through magnesium-dependent block of transient receptor potential melastatin 7 (TRPM7) channels

J Biol Chem. 2011 Nov 11;286(45):39328-35. doi: 10.1074/jbc.M111.264341. Epub 2011 Sep 16.

Abstract

Transient receptor potential melastatin 7 (TRPM7) channels represent the major magnesium-uptake mechanism in mammalian cells and are key regulators of cell growth and proliferation. They are expressed abundantly in a variety of human carcinoma cells controlling survival, growth, and migration. These characteristics are the basis for recent interest in the channel as a target for cancer therapeutics. We screened a chemical library of marine organism-derived extracts and identified waixenicin A from the soft coral Sarcothelia edmondsoni as a strong inhibitor of overexpressed and native TRPM7. Waixenicin A activity was cytosolic and potentiated by intracellular free magnesium (Mg(2+)) concentration. Mutating a Mg(2+) binding site on the TRPM7 kinase domain reduced the potency of the compound, whereas kinase deletion enhanced its efficacy independent of Mg(2+). Waixenicin A failed to inhibit the closely homologous TRPM6 channel and did not significantly affect TRPM2, TRPM4, and Ca(2+) release-activated Ca(2+) current channels. Therefore, waixenicin A represents the first potent and relatively specific inhibitor of TRPM7 ion channels. Consistent with TRPM7 inhibition, the compound blocked cell proliferation in human Jurkat T-cells and rat basophilic leukemia cells. Based on the ability of the compound to inhibit cell proliferation through Mg(2+)-dependent block of TRPM7, waixenicin A, or structural analogs may have cancer-specific therapeutic potential, particularly because certain cancers accumulate cytosolic Mg(2+).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Animals
  • Anthozoa / chemistry*
  • Binding Sites
  • Cell Proliferation / drug effects*
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Magnesium / metabolism*
  • Membrane Transport Modulators
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Rats
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*

Substances

  • Acetates
  • Diterpenes
  • Membrane Transport Modulators
  • TRPM Cation Channels
  • waixenicin A
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human
  • Trpm7 protein, rat
  • Magnesium