title: Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer.
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.
authors: 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.
authors: Charlotte
authors: C
authors: Dubois
authors: 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.
authors: Fabien
authors: F
authors: Vanden Abeele
authors: 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.
authors: V'yacheslav
authors: V
authors: Lehen'kyi
authors: 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.
authors: Dimitra
authors: D
authors: Gkika
authors: Inserm, INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet, Nice 06202, France.
authors: Basma
authors: B
authors: Guarmit
authors: 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.
authors: Gilbert
authors: G
authors: Lepage
authors: 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.
authors: Christian
authors: C
authors: Slomianny
authors: 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.
authors: Anne Sophie
authors: AS
authors: Borowiec
authors: 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.
authors: Gabriel
authors: G
authors: Bidaux
authors: Inserm, INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet, Nice 06202, France.
authors: Mohamed
authors: M
authors: Benahmed
authors: 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.
authors: Yaroslav
authors: Y
authors: Shuba
authors: 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.
authors: Natalia
authors: N
authors: Prevarskaya
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000368:Aged; D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D021381:Protein Transport; D034622:RNA Interference; D000071737:Stromal Interaction Molecule 1; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C530104:CCND1 protein, human; D015220:Calcium Channels; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C522867:Orai3 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019938:Cyclin D1; D016718:Arachidonic Acid