Targeting of short TRPM8 isoforms induces 4TM-TRPM8-dependent apoptosis in prostate cancer cells

Gabriel Bidaux (1) , Anne-Sophie Borowiec (2) , Charlotte Dubois (2) , Philippe Delcourt (2) , Céline Schulz (2) , Fabien Vanden Abeele (2) , Gilbert Lepage (2) , Emilie Desruelles (2) , Alexandre Bokhobza (2) , Etienne Dewailly (2) , Christian Slomianny (2) , Morad Roudbaraki (2) , Laurent Héliot (3) , Jean-Louis Bonnal (2) , Brigitte Mauroy (2) , Pascal Mariot (2) , Loïc Lemonnier (2) , Natalia Prevarskaya (2)

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
2 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
3 PhLAM - Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523

Since its cloning a decade ago, TRPM8 channel has emerged as a promising prognostic marker and a putative therapeutic target in prostate cancer (PCa). However, recent studies have brought to light the complexity of TRPM8 isoforms in PCa. Consequently, the respective role of each TRPM8 isoform needs to be deciphered prior to considering TRPM8 as an attractive therapeutic target. Full-length (6 transmembrane (TM)-domain) TRPM8 channel is overexpressed in early PCa and repressed in advanced prostate tumors whereas the localization of the truncated, 4TM-TRPM8 channel (4 transmembrane (TM)-domain), in the membranes of endoplasmic reticulum (ER) is independent of the pathogenic status of epithelial cells. In the same line, expression of non-channel cytoplasmic small TRPM8 isoforms (namely sM8) is conserved in cancer cells. In this study, we identify sM8s as putative regulator of PCa cell death. Indeed, suppression of sM8 isoforms was found to induce concomitantly ER stress, oxidative stress, p21 expression and apoptosis in human epithelial prostate cancer cells. We furthermore demonstrate that induction of such mechanisms required the activity of 4TM-TRPM8 channels at the ER-mitochondria junction. Our study thus suggests that targeting sM8 could be an appropriate strategy to fight prostate cancer.

Mots clés: TRPM8; ER calcium fluxes; mitochondria; prostate cancer; apoptosis

Domaines: Cancer; Biochimie, Biologie Moléculaire

Gabriel Bidaux, Anne-Sophie Borowiec, Charlotte Dubois, Philippe Delcourt, Céline Schulz, et al.. Targeting of short TRPM8 isoforms induces 4TM-TRPM8-dependent apoptosis in prostate cancer cells. Oncotarget, 2016, 7 (20), pp.29063-29080. ⟨10.18632/oncotarget.8666⟩. ⟨hal-03060359⟩