Targeting of short TRPM8 isoforms induces 4TM-TRPM8-dependent apoptosis in prostate cancer cells
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Gabriel Bidaux1,2,3,*, Anne-Sophie Borowiec1,2,*, Charlotte Dubois1,2, Philippe Delcourt1,2, Céline Schulz1,2, Fabien Vanden Abeele1,2, Gilbert Lepage1,2, Emilie Desruelles1,2, Alexandre Bokhobza1,2, Etienne Dewailly1,2, Christian Slomianny1,2, Morad Roudbaraki1,2, Laurent Héliot3, Jean-Louis Bonnal1,2, Brigitte Mauroy1,2, Pascal Mariot1,2, Loïc Lemonnier1,2, Natalia Prevarskaya1,2
1Inserm, U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d’Ascq, France
2Université des Sciences et Technologies de Lille (USTL), Villeneuve d’Ascq, France
3Laboratoire de Physique des Lasers, Atomes and Molécules, Equipe Biophotonique Cellulaire Fonctionnelle, Parc Scientifique de la Haute Borne, Villeneuve d’Ascq, France
*These authors contributed equally to this work
Gabriel Bidaux, email: email@example.com
Keywords: TRPM8, ER calcium fluxes, mitochondria, prostate cancer, apoptosis
Received: November 03, 2015 Accepted: March 29, 2016 Published: April 09, 2016
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.
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