TRPM4 channel is involved in regulating epithelial to mesenchymal transition, migration, and invasion of prostate cancer cell lines. Issue 3 (21st October 2018)

• Record Type: Journal Article
• Authors: Sagredo, Alfredo I.; Sagredo, Eduardo A.; Pola, Victor; Echeverría, César; Andaur, Rodrigo; Michea, Luis; Stutzin, Andrés; Simon, Felipe; Marcelain, Katherine; Armisén, Ricardo
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 3(2019:Mar.)
• Page Start: 2037
• Page End: 2050
• Publication Date: 2018-10-21
• Subjects: EMT -- invasion -- prostate cancer -- Snail1 -- TRPM4; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27371
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Transient Receptor Potential Melastatin 4 (TRPM4) is a Ca 2+ ‐activated and voltage‐dependent monovalent cation channel, which depolarizes the plasma cell membrane, thereby modulating Ca 2+ influx across Ca 2+ ‐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. Abstract : 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.