TRPM 4 regulates Akt/ GSK 3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

• Published in: Molecular oncology Vol. 12; no. 2; pp. 151 - 165
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Hoboken John Wiley & Sons, Inc 01.02.2018
• Subjects: AKT protein; AKT1 protein; Calcium-binding protein; Calmodulin; Catenin; Cell growth; Cell proliferation; Epidermal growth factor; Epidermal growth factor receptors; Immunoglobulins; Kinases; LEF protein; Localization; Mutation; Phosphorylation; Prostate cancer; Proteins; Transcription; Transient receptor potential proteins; Tumors; United States > US
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12100

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.