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

// Marie-Laure Plissonnier 1, 5, * , Sylvie Fauconnet 1, 2, * , Hugues Bittard 1, 2 , Christiane Mougin 1, 3 , Jean Rommelaere 4 and Isabelle Lascombe 1 1 EA3181, Universite Bourgogne Franche-Comte, LabEx LipSTIC ANR-11-LABX-0021, Besancon F-25030, France 2 Department of Urology, University Hospital of Besancon, Besancon F-25030, France 3 Department of Pathology, University Hospital of Besancon, Besancon F-25030, France 4 German Cancer Research Center Tumor Virology F010, Heidelberg 69120, Germany 5 Cancer Research Center of Lyon, INSERM U1052, Lyon F-69424, France * These authors contributed equally to this work Correspondence to: Isabelle Lascombe, email: isabelle.lascombe@univ-fcomte.fr Keywords: cervical cancer cells; apoptosis; PPAR; thiazolidinedione; TRAIL, HPV Received: July 22, 2017      Accepted: November 10, 2017      Published: November 22, 2017 ABSTRACT 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 via 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.