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
  • 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.
Products