Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression

Sana Kouba; Paul Buscaglia; Maxime Guéguinou; Sajida Ibrahim; Romain Félix; Roseline Guibon; Gaëlle Fromont; Natascha Pigat; Thierry Capiod; Christophe Vandier; Olivier Mignen; Marie Potier-Cartereau

doi:10.1016/j.ceca.2023.102794

Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression

Cell Calcium. 2023 Nov:115:102794. doi: 10.1016/j.ceca.2023.102794. Epub 2023 Aug 14.

Authors

Affiliations

¹ INSERM U1069, N2C: Nutrition, Croissance et Cancer, University of Tours, Tours, France.
² INSERM U1227, LBAI: Lymphocytes B, Autoimmunité et Immunotherapies, University of Bretagne Occidentale, Brest, France.
³ EA 7501, University of Tours - ERL 7001 LNOx - CNRS, GICC: Groupe Innovation et Ciblage Cellulaire, Tours, France.
⁴ INSERM U1069, N2C: Nutrition, Croissance et Cancer, University of Tours, Tours, France; Service d'Anatomie et cytologie pathologiques, Bretonneau, Centre Hospitalier Régional et Universitaire, Tours, France.
⁵ INSERM U1151, Institut Necker Enfants Malades, Universiy of Paris, 160 rue de Vaugirard, Paris 75015 France.
⁶ INSERM U1227, LBAI: Lymphocytes B, Autoimmunité et Immunotherapies, University of Bretagne Occidentale, Brest, France. Electronic address: olivier.mignen@univ-brest.fr.
⁷ INSERM U1069, N2C: Nutrition, Croissance et Cancer, University of Tours, Tours, France. Electronic address: marie.potier-cartereau@univ-tours.fr.

PMID: 37597301
DOI: 10.1016/j.ceca.2023.102794

Abstract

Prostate cancer (PCa) represents one of the most frequent diagnosed cancer in males worldwide. Due to routine screening tests and the efficiency of available treatments, PCa-related deaths have significantly decreased over the past decades. However, PCa remains a critical threat if detected at a late stage in which, cancer cells would have already detached from the primary tumor to spread and invade other parts of the body. Calcium (Ca²⁺) channels and their protein regulators are now considered as hallmarks of cancer and some of them have been well examined in PCa. Among these Ca²⁺ channels, isoform 3 of the ORAI channel family has been shown to regulate the proliferation of PCa cells via the Arachidonic Acid-mediated Ca²⁺ entry, requiring the involvement of STIM1 (Stromal Interaction Molecule 1). Still, no study has yet demonstrated a role of the "neglected" STIM2 isoform in PCa or if it may interact with ORAI3 to promote an oncogenic behavior. In this study, we demonstrate that ORAI3 and STIM2 are upregulated in human PCa tissues. In old KIMAP (Knock-In Mouse Prostate Adenocarcinoma) mice, ORAI3 and STIM2 mRNA levels were significantly higher than ORAI1 and STIM1. In vitro, we show that ORAI3-STIM2 interact under basal conditions in PC-3 cells. ORAI3 silencing increased Store Operated Ca²⁺ Entry (SOCE) and induced a significant increase of the cell population in G2/M phase of the cell cycle, consistent with the role of ORAI3 as a negative regulator of SOCE. Higher expression levels of CDK1-Y15/Cyclin B1 were detected and mitotic arrest-related death occurred after ORAI3 silencing, which resulted in activating Bax/Bcl-2-mediated apoptotic pathway and caspase-8 activation and cleavage. STIM2 and ORAI3 expression increased in M phase while STIM1 expression and SOCE amplitude significantly decreased. Taken together, ORAI3 -STIM2 complex allows a successful progression through mitosis of PCa cells by evading mitotic catastrophe.

Keywords: CDK1/Cyclin B1; Calcium signaling; Cell cycle; Mitotic catastrophe; ORAI3-STIM2; Prostate cancer.