Article Dans Une Revue Oncotarget Année : 2018

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

Résumé

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.

Domaines

Fichier principal
Vignette du fichier
26084-1012810-4-PB.pdf (4.17 Mo) Télécharger le fichier
Origine Publication financée par une institution
Licence
Loading...

Dates et versions

inserm-02102500 , version 1 (17-04-2019)

Licence

Identifiants

Citer

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, 2018, 9 (74), pp.33896-33911. ⟨10.18632/oncotarget.26084⟩. ⟨inserm-02102500⟩
164 Consultations
194 Téléchargements

Altmetric

Partager

  • More