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

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

  • Oncotarget. 2018 Sep 21;9(74):33896-33911. doi: 10.18632/oncotarget.26084.
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,  Monique N'Diaye 1 2
Affiliations

Affiliations

  • 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.
  • # Contributed equally.
PMID: 30338034 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.

Keywords

ABT-737; MCL-1; Store-operated calcium channels; mTORC1; ovarian cancer.

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