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

Marie-Laure Bonnefond 1 Romane Florent 1 Sophie Lenoir 2 Bernard Lambert 1, 3 Edwige Abeilard 1 Florence Giffard 1 Marie-Hélène Louis 1 Nicolas Elie 1, 4 Mélanie Briand 1, 5 Denis Vivien 2 Laurent Poulain 1 Pascal Gauduchon 1 Monique N'Diaye 1, *
* Corresponding author
1 Axe BioTICLA
ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
2 Équipe tPA et troubles neurovasculaires [Caen]
PhIND - Physiopathologie et imagerie des troubles neurologiques
3 Délégation Régionale Normandie du CNRS [Caen]
4 CMABio3 - Centre de Microscopie Appliquée à la Biologie [Caen]
5 CRB OvaRessources - Centre de Ressources Biologiques OvaRessources [Caen]
Abstract : 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.
Keywords : ovarian cancer Store-operated calcium channels mTORC1 MCL-1 ABT-737
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Marie-Laure Bonnefond, Romane Florent, Sophie Lenoir, Bernard Lambert, Edwige Abeilard, et al.. Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation. Oncotarget, Impact journals, 2018, 9 (74), pp.33896-33911. ⟨10.18632/oncotarget.26084⟩. ⟨inserm-02102500⟩

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