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

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+).

• Authors: Susanna Zierler, Guangmin Yao, Zheng Zhang, W Cedric Kuo, Peter Pörzgen, Reinhold Penner, F David Horgen, Andrea Fleig
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 45 Pg. 39328-35 (Nov 11 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21926172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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