Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.: Orai1 in apoptosis resistance of prostate cancer

Abstract : The molecular nature of calcium (Ca(2+))-dependent mechanisms and the ion channels having a major role in the apoptosis of cancer cells remain a subject of debate. Here, we show that the recently identified Orai1 protein represents the major molecular component of endogenous store-operated Ca(2+) entry (SOCE) in human prostate cancer (PCa) cells, and constitutes the principal source of Ca(2+) influx used by the cell to trigger apoptosis. The downregulation of Orai1, and consequently SOCE, protects the cells from diverse apoptosis-inducing pathways, such as those induced by thapsigargin (Tg), tumor necrosis factor α, and cisplatin/oxaliplatin. The transfection of functional Orai1 mutants, such as R91W, a selectivity mutant, and L273S, a coiled-coil mutant, into the cells significantly decreased both SOCE and the rate of Tg-induced apoptosis. This suggests that the functional coupling of STIM1 to Orai1, as well as Orai1 Ca(2+)-selectivity as a channel, is required for its pro-apoptotic effects. We have also shown that the apoptosis resistance of androgen-independent PCa cells is associated with the downregulation of Orai1 expression as well as SOCE. Orai1 rescue, following Orai1 transfection of steroid-deprived cells, re-established the store-operated channel current and restored the normal rate of apoptosis. Thus, Orai1 has a pivotal role in the triggering of apoptosis, irrespective of apoptosis-inducing stimuli, and in the establishment of an apoptosis-resistant phenotype in PCa cells.
Type de document :
Article dans une revue
Cell Death and Disease , Nature Publishing Group, 2010, 1 (9), pp.e75. 〈10.1038/cddis.2010.52〉
Liste complète des métadonnées

Littérature citée [32 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00520275
Contributeur : Matthieu Flourakis <>
Soumis le : mercredi 22 septembre 2010 - 18:11:27
Dernière modification le : lundi 6 novembre 2017 - 01:00:31
Document(s) archivé(s) le : jeudi 23 décembre 2010 - 03:13:29

Fichier

Flourakis_et_al_Sept_2010.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

Matthieu Flourakis, V'Yacheslav Lehen'Kyi, Benjamin Beck, Maylis Raphael, Matthieu Vandenberghe, et al.. Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.: Orai1 in apoptosis resistance of prostate cancer. Cell Death and Disease , Nature Publishing Group, 2010, 1 (9), pp.e75. 〈10.1038/cddis.2010.52〉. 〈inserm-00520275〉

Partager

Métriques

Consultations de la notice

270

Téléchargements de fichiers

105