Research Papers:

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

Marie-Laure Bonnefond, Romane Florent, Sophie Lenoir, Bernard Lambert, Edwige Abeilard, Florence Giffard, Marie-Hélène Louis, Nicolas Elie, Mélanie Briand, Denis Vivien, Laurent Poulain, Pascal Gauduchon and Monique N’Diaye _

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Oncotarget. 2018; 9:33896-33911. https://doi.org/10.18632/oncotarget.26084

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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

Correspondence to:

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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