Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation
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Marie-Laure Bonnefond1,2,*, Romane Florent1,2,*, Sophie Lenoir3, Bernard Lambert1,2,4, Edwige Abeilard1,2, Florence Giffard1,2, Marie-Hélène Louis1,2, Nicolas Elie1,5, Mélanie Briand1,2,6, Denis Vivien3, Laurent Poulain1,2, Pascal Gauduchon1,2 and Monique N’Diaye1,2
1Normandie University, UNICAEN, INSERM U1086 ANTICIPE, Interdisciplinary Research Unit for Cancer Prevention and Treatment, BioTICLA Axis, Biology and Innovative Therapeutics for Ovarian Cancers, Caen, France
2UNICANCER, François Baclesse Cancer Center, BioTICLA Laboratory, Caen, France
3Normandie University, UNICAEN, INSERM UMR-S 1237, Physiopathologie et Imagerie des Troubles Neurologiques (PhIND), tPA and Neurovascular Disorders Team, Caen, France
4Délégation Régionale de Normandie, CNRS, Caen, France
5Normandie University, UNICAEN, Centre de Microscopie Appliqué à la Biologie, CMabio3, Structure Fédérative 4206 ICORE, Caen, France
6Centre de Ressources Biologiques, OvaRessources, François Baclesse Cancer Center, Caen, France
*These authors have contributed equally to this work
Monique N’Diaye, email: [email protected]
Keywords: ovarian cancer; Store-operated calcium channels; mTORC1; MCL-1; ABT-737
Received: October 27, 2017 Accepted: August 04, 2018 Published: September 21, 2018
The anti-apoptotic proteins Bcl-xL 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-xL 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-xL 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-xL strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma.
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