Open AccessTRPM 4 regulates Akt/ GSK 3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells
Author(s) -
Sagredo Alfredo I.,
Sagredo Eduardo A.,
Cappelli Claudio,
Báez Pablo,
Andaur Rodrigo E.,
Blanco Constanza,
Tapia Julio C.,
Echeverría César,
Cerda Oscar,
Stutzin Andrés,
Simon Felipe,
Marcelain Katherine,
Armisén Ricardo
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12100
Subject(s) - protein kinase b , lncap , phosphorylation , prostate cancer , cancer research , signal transduction , chemistry , microbiology and biotechnology , beta catenin , biology , cancer , wnt signaling pathway , genetics
Increased expression of the TRPM 4 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 TRPM 4 levels leads to the reduced proliferation of PC 3 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, TRPM 4 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, TRPM 4 overexpression in LNC aP cells increases the Ser9 inhibitory phosphorylation of GSK ‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC 3 cells with reduced levels of TRPM 4 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 TRPM 4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐ EGFR axis, linking TRPM 4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM 4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.