1. The antidiabetic drug ciglitazone induces high grade bladder cancer cells apoptosis through the up-regulation of TRAIL
- Author
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Sylvie Fauconnet, Hugues Bittard, Isabelle Lascombe, Marie-Laure Plissonnier, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'urologie, andrologie et transplantation rénale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Service de Néphrologie et Urologie, and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques
- Subjects
MESH: CASP8 and FADD-Like Apoptosis Regulating Protein ,Cell cycle checkpoint ,MESH : Antineoplastic Combined Chemotherapy Protocols ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Peroxisome proliferator-activated receptor ,Apoptosis ,MESH: Thiazolidinediones ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,Inhibitor of Apoptosis Proteins ,TNF-Related Apoptosis-Inducing Ligand ,Mice ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,MESH: Up-Regulation ,MESH : Inhibitor of Apoptosis Proteins ,MESH: Animals ,MESH : Transcriptional Activation ,lcsh:Science ,MESH : Up-Regulation ,Apoptotic Signaling ,chemistry.chemical_classification ,0303 health sciences ,Bladder Cancer and Urothelial Neoplasias of the Urinary Tract ,MESH: Proteasome Endopeptidase Complex ,MESH : Mitosis ,3. Good health ,Cell biology ,Up-Regulation ,MESH: Antineoplastic Combined Chemotherapy Protocols ,Oncology ,030220 oncology & carcinogenesis ,Caspases ,Medicine ,MESH: TNF-Related Apoptosis-Inducing Ligand ,MESH : Neoplasm Grading ,BH3 Interacting Domain Death Agonist Protein ,MESH : PPAR gamma ,G2 Phase ,Transcriptional Activation ,MESH: Xenograft Model Antitumor Assays ,MESH: Enzyme Activation ,Drug Research and Development ,MESH : Cell Membrane ,MESH: BH3 Interacting Domain Death Agonist Protein ,MESH : Xenograft Model Antitumor Assays ,03 medical and health sciences ,Ciglitazone ,Survivin ,MESH : Proteasome Endopeptidase Complex ,Humans ,Biology ,MESH: Humans ,MESH: Caspases ,MESH : Humans ,lcsh:R ,Cell Membrane ,MESH: Inhibitor of Apoptosis Proteins ,MESH : Hypoglycemic Agents ,Enzyme Activation ,Genitourinary Tract Tumors ,chemistry ,MESH: PPAR gamma ,Urinary Bladder Neoplasms ,Cancer cell ,lcsh:Q ,Thiazolidinediones ,Neoplasm Grading ,MESH : Apoptosis ,MESH: Receptors, Death Domain ,MESH: Signal Transduction ,lcsh:Medicine ,MESH: Neoplasm Grading ,MESH : TNF-Related Apoptosis-Inducing Ligand ,Molecular Cell Biology ,MESH : G2 Phase ,Signaling in Cellular Processes ,Cyclin B1 ,Caspase ,Apoptotic Signaling Cascade ,Multidisciplinary ,biology ,Cell Death ,MESH : Receptors, Death Domain ,Receptors, Death Domain ,Bladder Cancer ,Signaling Cascades ,MESH: Urinary Bladder Neoplasms ,MESH : Thiazolidinediones ,MESH : Urinary Bladder Neoplasms ,Signal Transduction ,Research Article ,Proteasome Endopeptidase Complex ,Drugs and Devices ,MESH: Cell Line, Tumor ,Urology ,Mitosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH: Hypoglycemic Agents ,Cell Line, Tumor ,MESH : Mice ,Animals ,Hypoglycemic Agents ,MESH : BH3 Interacting Domain Death Agonist Protein ,MESH: Mice ,030304 developmental biology ,MESH : Signal Transduction ,MESH : Cell Line, Tumor ,MESH: Apoptosis ,Cancers and Neoplasms ,MESH : CASP8 and FADD-Like Apoptosis Regulating Protein ,MESH: Mitosis ,Xenograft Model Antitumor Assays ,PPAR gamma ,MESH: G2 Phase ,biology.protein ,Cancer research ,MESH: Transcriptional Activation ,MESH : Animals ,MESH : Caspases ,MESH : Enzyme Activation ,MESH: Cell Membrane - Abstract
International audience; BACKGROUND: Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Using RT4 (derived from a well differentiated grade I papillary tumor) and T24 (derived from an undifferentiated grade III carcinoma) bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21(waf1/CIP1) and p27(Kip1) in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism. CONCLUSIONS/SIGNIFICANCE: Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.
- Published
- 2011
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