Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function
Gabriel Bidaux, … , Roman Skryma, Natalia Prevarskaya
Gabriel Bidaux, … , Roman Skryma, Natalia Prevarskaya
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1647-1657. https://doi.org/10.1172/JCI30168.
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Research Article

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

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

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Figure 8

Schematic diagram summarizing the principal findings of this study and showing a simplified representation of differential TRPM8 localization and function depending on the AR activity, differentiation, and oncogenic status of human prostate epithelial cells.

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Schematic diagram summarizing the principal findings of this study and s...
(A) General pattern of nondifferentiated TA/I cells and dedifferentiated metastatic cells. In these cells AR level was low, and only the ERTRPM8 isoform was expressed in the ER membrane. ERTRPM8 functioned as a Ca2+-release ER channel, which, by depleting ER stores, activated SOC localized on the PM. Under these conditions, TRPM8 agonists did not induce classical PMTRPM8-mediated current. (B) Normal, fully differentiated prostate cell with an apical secretory phenotype. In these cells, with high AR levels, the AR-dependent classical TRPM8 channel was expressed on both ER and PM. Under these conditions, TRPM8 agonists may induce not only SOCE, but also substantial PMTRPM8-mediated current. (C) Differentiated apical secretory in situ cancer cells. In these cells, with enhanced AR activity, the AR-dependent classical TRPM8 channel was overexpressed and TRPM8 agonists induced high levels of PMTRPM8-mediated current. iTRPM8 traces are schematic.