title: Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells.
abstract: Breast cancer (BC) is the leading cancer in the world in terms of incidence and mortality in women. However, the mechanism by which BC develops remains largely unknown. The increase in cytosolic free Ca(2+) can result in different physiological changes including cell growth and death. Orai isoforms are highly Ca(2+) selective channels. In the present study, we analyzed Orai3 expression in normal and cancerous breast tissue samples, and its role in MCF-7 BC and normal MCF-10A mammary epithelial cell lines. We found that the expression of Orai3 mRNAs was higher in BC tissues and MCF-7 cells than in normal tissues and MCF-10A cells. Down-regulation of Orai3 by siRNA inhibited MCF-7 cell proliferation and arrested cell cycle at G1 phase. This phenomenon is associated with a reduction in CDKs 4/2 (cyclin-dependent kinases) and cyclins E and D1 expression and an accumulation of p21(Waf1/Cip1) (a cyclin-dependent kinase inhibitor) and p53 (a tumor-suppressing protein). Orai3 was also involved in MCF-7 cell survival. Furthermore, Orai3 mediated Ca(2+) entry and contributed to intracellular calcium concentration ([Ca(2+)](i)). In MCF-10A cells, silencing Orai3 failed to modify [Ca(2+)](i), cell proliferation, cell-cycle progression, cyclins (D1, E), CDKs (4, 2), and p21(Waf1/Cip1) expression. Our results provide strong evidence for a significant effect of Orai3 on BC cell growth in vitro and show that this effect is associated with the induction of cell cycle and apoptosis resistance. Our study highlights a possible role of Orai3 as therapeutic target in BC therapy.
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, JE 2530: Canaux ioniques dans le Cancer du Sein, Faculté des Sciences, UPJV, Amiens, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Faouzi
authors.forename: Frederic
authors.initials: F
authors.lastname: Hague
authors.forename: Marie
authors.initials: M
authors.lastname: Potier
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ahidouch
authors.forename: Henri
authors.initials: H
authors.lastname: Sevestre
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C522867:Orai3 protein, human; D034741:RNA, Small Interfering; D018844:Cyclin-Dependent Kinases