期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 45, 页码 39328-39335出版社
ELSEVIER
DOI: 10.1074/jbc.M111.264341
关键词
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资金
- National Institutes of Health [P01GM078195, P20 RR-016467]
- University of Hawaii [5G12 RR003061-22]
- American Society of Pharmacognosy
- Austrian Science Fund [J2784]
- Austrian Science Fund (FWF) [J2784] Funding Source: Austrian Science Fund (FWF)
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 (Mg2+) concentration. Mutating a Mg2+ binding site on the TRPM7 kinase domain reduced the potency of the compound, whereas kinase deletion enhanced its efficacy independent of Mg2+. Waixenicin A failed to inhibit the closely homologous TRPM6 channel and did not significantly affect TRPM2, TRPM4, and Ca2+ release-activated Ca2+ 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 Mg2+-dependent block of TRPM7, waixenicin A, or structural analogs may have cancer-specific therapeutic potential, particularly because certain cancers accumulate cytosolic Mg2+.
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