Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation

// Marie-Laure Bonnefond 1, 2, * , Romane Florent 1, 2, * , Sophie Lenoir 3 , Bernard Lambert 1, 2, 4 , Edwige Abeilard 1, 2 , Florence Giffard 1, 2 , Marie-Hélène Louis 1, 2 , Nicolas Elie 1, 5 , Mélanie Briand 1, 2, 6 , Denis Vivien 3 , Laurent Poulain 1, 2 , Pascal Gauduchon 1, 2 and Monique N’Diaye 1, 2 1 Normandie University, UNICAEN, INSERM U1086 ANTICIPE, Interdisciplinary Research Unit for Cancer Prevention and Treatment, BioTICLA Axis, Biology and Innovative Therapeutics for Ovarian Cancers, Caen, France 2 UNICANCER, François Baclesse Cancer Center, BioTICLA Laboratory, Caen, France 3 Normandie University, UNICAEN, INSERM UMR-S 1237, Physiopathologie et Imagerie des Troubles Neurologiques (PhIND), tPA and Neurovascular Disorders Team, Caen, France 4 Délégation Régionale de Normandie, CNRS, Caen, France 5 Normandie University, UNICAEN, Centre de Microscopie Appliqué à la Biologie, CMabio3, Structure Fédérative 4206 ICORE, Caen, France 6 Centre de Ressources Biologiques, OvaRessources, François Baclesse Cancer Center, Caen, France * These authors have contributed equally to this work Correspondence to: Monique N’Diaye, email: monique.ndiaye@unicaen.fr Keywords: ovarian cancer; Store-operated calcium channels; mTORC1; MCL-1; ABT-737 Received: October 27, 2017      Accepted: August 04, 2018      Published: September 21, 2018 ABSTRACT The anti-apoptotic proteins Bcl-x L and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-x L activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-x L strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-x L strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma.