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Transient Receptor Potential Melastatin 4 (TRPM4) is a Ca2+‐activated and voltage‐dependent monovalent cation channel, which depolarizes the plasma cell membrane, thereby modulating Ca2+ influx across Ca2+‐permeable pathways. TRPM4 is involved in different physiological processes such as T cell activation and the migration of endothelial and certain immune cells. Overexpression of this channel has been reported in various types of tumors including prostate cancer. In this study, a significant overexpression of TRPM4 was found only in samples from cancer with a Gleason score higher than 7, which are more likely to spread. To evaluate whether TRPM4 overexpression was related to the spreading capability of tumors, TRPM4 was knockdown by using shRNAs in PC3 prostate cancer cells and the effect on cellular migration and invasion was analyzed. PC3 cells with reduced levels of TRPM4 (shTRPM4) display a decrease of the migration/invasion capability. A reduction in the expression of Snail1, a canonical epithelial to mesenchymal transition (EMT) transcription factor, was also observed. Consistently, these cells showed a significant change in the expression of key EMT markers such as MMP9, E‐cadherin/N‐cadherin, and vimentin, indicating a partial reversion of the EMT process. Whereas, the overexpression of TRPM4 in LnCaP cells resulted in increased levels of Snail1, reduction in the expression of E‐cadherin and increase in their migration potential. This study suggests a new and indirect mechanism of regulation of migration/invasion process by TRPM4 in prostate cancer cells, by inducing the expression of Snail1 gene and consequently, increasing the EMT. TRPM4 expression and function modulate the inhibitory phosphorylation of GSK‐3β promoting the β‐Catenin stability and its transcriptional activity on several genes involved in proliferation as Myc and CCND1 and EMT markers, such as Zeb, Vimentin, and Snail1. Also, this effect could regulate the stability of Snail1, promoting the invasive phenotype thought the regulation of the EMT markers as E‐Cadherin, N‐Cadherin, MMPs, and others. Interestingly, TRPM4 it is involved directly in the focal adhesion turnover promoting the cellular migration. These finding highlight this ion channel as a new potential target for future cancer therapies. [ABSTRACT FROM AUTHOR]

Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β‐catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β‐catenin phosphorylated population and reduces the phosphorylation of GSK‐3β at Ser9, suggesting an increase in β‐catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK‐3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐EGFR axis, linking TRPM4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer. [ABSTRACT FROM AUTHOR]

Altered expression of some members of the TRP ion channel superfamily has been associated with the development of pathologies like cancer. In particular, TRPM4 levels are reportedly elevated in diffuse large B-cell non-Hodgkin lymphoma, prostate, and cervical cancer. However, whether such changes in TRPM4 expression may be relevant to genesis or progression of cancer remains unknown. Here we show that reducing TRPM4 expression decreases proliferation of HeLa cells, a cervical cancer-derived cell line. In this cell line, constitutive TRPM4 silencing promoted GSK-3β-dependent degradation of β-catenin and reduced β-catenin/Tcf/Lef-dependent transcription. Conversely, overexpression of TRPM4 in T-REx 293 cells (a HEK293-derived cell line) increased cell proliferation and β-catenin levels. Our results identify TRPM4 as an important, unanticipated regulator of the β-catenin pathway, where aberrant signaling is frequently associated with cancer. J. Cell. Physiol. 226: 103-109, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]