Cell death and restoration of TRAIL-sensitivity by ciglitazone in resistant cervical cancer cells.

Fiche publication

Date publication

décembre 2017

Journal

Oncotarget

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BITTARD Hugues , Dr LASCOMBE Isabelle , Dr FAUCONNET Sylvie

Tous les auteurs :
Plissonnier ML, Fauconnet S, Bittard H, Mougin C, Rommelaere J, Lascombe I

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29296202

Résumé

Known activators of the Peroxisome Proliferator-Activated Receptor γ (PPARγ), thiazolidinediones (TZD) induce apoptosis in a variety of cancer cells through dependent and/or independent mechanisms of the receptor. We tested a panel of TZD (Rosiglitazone, Pioglitazone, Ciglitazone) to shed light on their potential therapeutic effects on three cervical cancer cell lines (HeLa, Ca Ski, C-33 A). In these cells, only ciglitazone triggered apoptosis through PPARγ-independent mechanisms and in particular both extrinsic and intrinsic pathways in Ca Ski cells containing Human PapillomaVirus (HPV) type 16. It also inhibits cervical cancer xenograft development in nude mice. Ciglitazone kills cervical cancer cells by activating death receptor signalling pathway, caspase cascade and BH3 interacting-domain death agonist (Bid) cleavage through the up-regulation of Death Receptor 4 (DR4)/DR5 and soluble and membrane-bound TNF related apoptosis inducing ligand (TRAIL). Importantly, the drug let TRAIL-resistant Ca Ski cells to respond to TRAIL through the downregulation of cellular FLICE-Like Inhibitory Protein (c-FLIP) level. For the first time, we revealed that ciglitazone is able to decrease E6 viral oncoprotein expression known to block TRAIL pathway and this was associated with cell death. Our results highlight the capacity of ciglitazone to restore TRAIL sensitivity and to prevent E6 blocking action to induce apoptosis in cervical cancer cells.