Increase in Serum Ca ^2+/Mg ²⁺ Ratio Promotes Proliferation of Prostate Cancer Cells by Activating TRPM7 Channels*

Abstract

Background: Mg ²⁺ concentration regulates MagNuM channels; however, their role in prostate cancer is not known.

Results: TRPM7 functions as an endogenous MagNuM channel, which facilitates Ca ²⁺ entry at low Mg ²⁺ levels and promotes cell proliferation.

Conclusion: Alteration in Ca ²⁺/Mg ²⁺ ratio could lead to prostate cancer.

Significance: Learning how extra/intracellular Ca ²⁺/Mg ²⁺ ratio is regulated is crucial for understanding and/or diagnosis of prostate cancer.

Abstract

TRPM7 is a novel magnesium-nucleotide-regulated metal current (MagNuM) channel that is regulated by serum Mg ²⁺ concentrations. Changes in Mg ²⁺ concentration have been shown to alter cell proliferation in various cells; however, the mechanism and the ion channel(s) involved have not yet been identified. Here we demonstrate that TRPM7 is expressed in control and prostate cancer cells. Supplementation of intracellular Mg-ATP or addition of external 2-aminoethoxydiphenyl borate inhibited MagNuM currents. Furthermore, silencing of TRPM7 inhibited whereas overexpression of TRPM7 increased endogenous MagNuM currents, suggesting that these currents are dependent on TRPM7. Importantly, although an increase in the serum Ca ²⁺/Mg ²⁺ ratio facilitated Ca ²⁺ influx in both control and prostate cancer cells, a significantly higher Ca ²⁺ influx was observed in prostate cancer cells. TRPM7 expression was also increased in cancer cells, but its expression was not dependent on the Ca ²⁺/Mg ²⁺ ratio per se. Additionally, an increase in the extracellular Ca ²⁺/Mg ²⁺ ratio led to a significant increase in cell proliferation of prostate cancer cells when compared with control cells. Consistent with these results, age-matched prostate cancer patients also showed a subsequent increase in the Ca ²⁺/Mg ²⁺ ratio and TRPM7 expression. Altogether, we provide evidence that the TRPM7 channel has an important role in prostate cancer and have identified that the Ca ²⁺/Mg ²⁺ ratio could be essential for the initiation/progression of prostate cancer.