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.
Highlights
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide [1]
We revealed that ciglitazone is able to decrease E6 viral oncoprotein expression known to block TNF related apoptosis inducing ligand (TRAIL) pathway and this was associated with cell death
We investigated the pro-apoptotic activity of TZD in several cervical cancer cell lines (HeLa, Ca Ski, C-33 A) and demonstrated that only ciglitazone individual treatment induced Ca Ski cell apoptosis through Peroxisome Proliferator-Activated Receptor γ (PPARγ)-independent mechanisms
Summary
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide [1]. Two virally encoded oncoproteins E6 and E7 contribute to carcinogenesis by decreasing pivotal cell signalling components, including the tumour suppressors p53 and pRb that lead to the dysregulation of cell proliferation, apoptosis and genome instability [3]. HPV E7 protein interacts with pRb, inducing its proteolytic degradation leading to the destabilization and the disruption of Rb/E2F repressor complexes which results in increased transcription of E2F-responsive genes and S-phase cell cycle progression [4]. The development www.impactjournals.com/oncotarget of therapeutic approaches which can restore the cellular death pathways inactivated by the viral oncoproteins, appears to be fundamental for the clinical treatment of HPV-induced cervical cancer
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