Abstract
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.
Highlights
Prostate cancer is one of the most frequently diagnosed malignancies and the fifth cause of cancerrelated deaths in men (Torre et al, 2015)
Schinke et al (2014) showed that the TRPM4 gene is involved in the progression of the androgen-independent growth stage, a late step in the progression of this tumor with no satisfactory treatment, indicating that this gene is an important candidate for study as a possible target for therapy in these patients
Using a siRNA against TRPM4, the primary human prostate epithelial cells and DU145 cells display an increase in SOCE, but no effect was observed in prostatic carcinoma cell line 3 (PC3) cells
Summary
Prostate cancer is one of the most frequently diagnosed malignancies and the fifth cause of cancerrelated deaths in men (Torre et al, 2015). The stimulation of the Wnt/canonical pathway by specific ligands (Rao and Ku€hl, 2010), activating mutations on the b-catenin sequence or inactivation of GSK-3b by specific phosphorylation at Ser, stabilizes b-catenin This promotes its translocation into the nucleus and interaction with members of the Tcf/Lef family of transcription factors (Mosimann et al, 2009), leading to the expression of genes involved in proliferation, apoptosis, and invasion, among other important processes for cancer progression (Clevers, 2006; Klaus and Birchmeier, 2008).
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