Cell death and restoration of TRAIL-sensitivity by ciglitazone in resistant cervical cancer cells
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Marie-Laure Plissonnier1,5,*, Sylvie Fauconnet1,2,*, Hugues Bittard1,2, Christiane Mougin1,3, Jean Rommelaere4 and Isabelle Lascombe1
1EA3181, Université Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, Besançon F-25030, France
2Department of Urology, University Hospital of Besançon, Besançon F-25030, France
3Department of Pathology, University Hospital of Besançon, Besançon F-25030, France
4German Cancer Research Center Tumor Virology F010, Heidelberg 69120, Germany
5Cancer Research Center of Lyon, INSERM U1052, Lyon F-69424, France
*These authors contributed equally to this work
Isabelle Lascombe, email: firstname.lastname@example.org
Keywords: cervical cancer cells; apoptosis; PPAR; thiazolidinedione; TRAIL, HPV
Received: July 22, 2017 Accepted: November 10, 2017 Published: November 22, 2017
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.
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