title: 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.affiliation: The Queen's Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Zierler
authors.forename: Guangmin
authors.initials: G
authors.lastname: Yao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: W Cedric
authors.initials: WC
authors.lastname: Kuo
authors.forename: Peter
authors.initials: P
authors.lastname: Pörzgen
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.forename: F David
authors.initials: FD
authors.lastname: Horgen
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008274:Magnesium / Q000378:metabolism*; D049990:Membrane Transport Modulators; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D051381:Rats; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000085:Acetates; D004224:Diterpenes; D049990:Membrane Transport Modulators; D050053:TRPM Cation Channels; C568854:waixenicin A; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; C486584:Trpm7 protein, rat; D008274:Magnesium