Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function

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Abstract

In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer (PCa). However, the mechanisms of prostate-specific regulation and functional evolution of TRPM8 during PCa progression remain unclear. Here we show, for the first time to our knowledge, that only secretory mature differentiated human prostate primary epithelial (PrPE) luminal cells expressed functional plasma membrane TRPM8 (PMTRPM8) channels. Moreover, PCa epithelial cells obtained from in situ PCa were characterized by a significantly stronger PMTRPM8-mediated current than that in normal cells. This PMTRPM8 activity was abolished in dedifferentiated PrPE cells that had lost their luminal secretory phenotype. However, we found that in contrast to PMTRPM8, endoplasmic reticulum TRPM8 (ERTRPM8) retained its function as an ER Ca2+ release channel, independent of cell differentiation. We hypothesize that the constitutive activity of ERTRPM8 may result from the expression of a truncated TRPM8 splice variant. Our study provides insight into the role of TRPM8 in PCa progression and suggests that TRPM8 is a potentially attractive target for therapeutic intervention: specific inhibition of either ERTRPM8 or PMTRPM8 may be useful, depending on the stage and androgen sensitivity of the targeted PCa.

Authors

Gabriel Bidaux, Matthieu Flourakis, Stéphanie Thebault, Alexander Zholos, Benjamin Beck, Dimitra Gkika, Morad Roudbaraki, Jean-Louis Bonnal, Brigitte Mauroy, Yaroslav Shuba, Roman Skryma, Natalia Prevarskaya