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Cancer Cell. 2014 Jul 14;26(1):19-32. doi: 10.1016/j.ccr.2014.04.025. Epub 2014 Jun 19.

Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer.

Author information

1
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq 59656, France.
2
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq 59656, France. Electronic address: Fabien.vanden-abeele@inserm.fr.
3
Inserm, INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet, Nice 06202, France.
4
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq 59656, France; Bogomoletz Institute of Physiology and International Centre of Molecular Physiology of the National Academy of Sciences of Ukraine, Kiev 01024, Ukraine.
5
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq 59656, France. Electronic address: natacha.prevarskaya@univ-lille1.fr.

Abstract

ORAI family channels have emerged as important players in malignant transformation, yet the way in which they reprogram cancer cells remains elusive. Here we show that the relative expression levels of ORAI proteins in prostate cancer are different from that in noncancerous tissue. By mimicking ORAI protein remodeling observed in primary tumors, we demonstrate in in vitro models that enhanced ORAI3 expression favors heteromerization with ORAI1 to form a novel channel. These channels support store-independent Ca(2+) entry, thereby promoting cell proliferation and a smaller number of functional homomeric ORAI1-based store-operated channels, which are important in supporting susceptibility to apoptosis. Thus, our findings highlight disrupted dynamic equilibrium of channel-forming proteins as an oncogenic mechanism.

PMID:
24954132
DOI:
10.1016/j.ccr.2014.04.025
[Indexed for MEDLINE]
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