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

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

doi:10.18632/oncotarget.26084

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.

Highlights

Despite its low incidence, epithelial ovarian carcinoma (EOC) is the fifth-leading cause of cancerrelated deaths in women
We investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression
Its effect on mTORC1 and Mcl-1 was mimicked by the potent store-operated calcium entry (SOCE) inhibitor, YM58483, which triggered apoptosis when combined with ABT-737

Summary

Introduction

Epithelial ovarian carcinoma (EOC) is the fifth-leading cause of cancerrelated deaths in women. Escape from apoptosis is one of the major hallmarks of cancer cells and is frequently due to alteration of the ratio of [anti- versus pro-apoptotic] members of the Bcl-2 family, which leads to an increase in apoptotic threshold during oncogenic stress [3] This altered ratio could be a therapeutic opportunity and it is widely accepted that targeting anti-apoptotic members is a relevant strategy to induce apoptosis in many types of cancer [4]. Our group previously showed that the anti-apoptotic proteins Mcl-1 and Bcl-xL were able to cooperate to allow ovarian carcinoma cells to overcome apoptosis, as their concomitant inhibition was sufficient to induce cell death [5,6,7] These proteins are considered as relevant targets for the treatment of chemoresistant ovarian cancers, and the identification of adequate strategies for their efficient inhibition constitutes an exciting challenge

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