Increase in serum Ca2+/Mg2+ ratio promotes proliferation of prostate cancer cells by activating TRPM7 channels.
Increase in serum Ca2+/Mg2+ ratio promotes proliferation of prostate cancer cells by activating TRPM7 channels.
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DOI：
10.1074/jbc.m112.393918
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发表时间：
2013-01-04
期刊：
影响因子：
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通讯作者：
Singh BB
中科院分区：
文献类型：
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作者：
Sun Y;Selvaraj S;Varma A;Derry S;Sahmoun AE;Singh BB
背景：Mg 2+浓度调节MagNuM通道;然而，它们在前列腺癌中的作用尚不清楚。结果：TRPM 7作为内源性MagNuM通道发挥功能，在低Mg 2+水平下促进Ca 2+内流，促进细胞增殖。结论：Ca 2 +/Mg 2+比值的改变可导致前列腺癌的发生。意义：了解细胞外/细胞内Ca 2 +/Mg 2+比例如何调节对于了解和/或诊断前列腺癌至关重要。TRPM 7是一种新型的镁核苷酸调节金属电流（MagNuM）通道，受血清Mg 2+浓度的调节。Mg 2+浓度的变化已被证明会改变各种细胞中的细胞增殖;然而，其机制和所涉及的离子通道尚未确定。在这里，我们证明了TRPM 7在对照和前列腺癌细胞中表达。补充细胞内Mg-ATP或添加外部2-氨基乙氧基二苯基硼酸盐抑制MagNuM电流。此外，TRPM 7的沉默抑制而TRPM 7的过表达增加内源性MagNuM电流，表明这些电流依赖于TRPM 7。重要的是，虽然在对照组和前列腺癌细胞中，血清Ca 2 +/Mg 2+比值的增加促进了Ca 2+内流，但在前列腺癌细胞中观察到显著更高的Ca 2+内流。TRPM 7在癌细胞中的表达也增加，但其表达不依赖于Ca 2 +/Mg 2+比率本身。此外，与对照细胞相比，细胞外Ca 2 +/Mg 2+比率的增加导致前列腺癌细胞的细胞增殖显著增加。与这些结果一致，年龄匹配的前列腺癌患者也显示出随后的Ca 2 +/Mg 2+比率和TRPM 7表达增加。总之，我们提供的证据表明TRPM 7通道在前列腺癌中具有重要作用，并已确定Ca 2 +/Mg 2+比值可能是前列腺癌发生/发展所必需的。
Background: Mg2+ concentration regulates MagNuM channels; however, their role in prostate cancer is not known. Results: TRPM7 functions as an endogenous MagNuM channel, which facilitates Ca2+ entry at low Mg2+ levels and promotes cell proliferation. Conclusion: Alteration in Ca2+/Mg2+ ratio could lead to prostate cancer. Significance: Learning how extra/intracellular Ca2+/Mg2+ ratio is regulated is crucial for understanding and/or diagnosis of prostate cancer. TRPM7 is a novel magnesium-nucleotide-regulated metal current (MagNuM) channel that is regulated by serum Mg2+ concentrations. Changes in Mg2+ 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 Ca2+/Mg2+ ratio facilitated Ca2+ influx in both control and prostate cancer cells, a significantly higher Ca2+ influx was observed in prostate cancer cells. TRPM7 expression was also increased in cancer cells, but its expression was not dependent on the Ca2+/Mg2+ ratio per se. Additionally, an increase in the extracellular Ca2+/Mg2+ 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 Ca2+/Mg2+ ratio and TRPM7 expression. Altogether, we provide evidence that the TRPM7 channel has an important role in prostate cancer and have identified that the Ca2+/Mg2+ ratio could be essential for the initiation/progression of prostate cancer.