title: The antidiabetic drug ciglitazone induces high grade bladder cancer cells apoptosis through the up-regulation of TRAIL.
abstract: 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.
  
  
  RESULTS
  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
  Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Médicales et Pharmaceutiques, Equipe d'Accueil 3181 - Institut Fédératif de Recherche N°133, Université de Franche - Comté, Besançon, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Plissonnier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fauconnet
authors.forename: Hugues
authors.initials: H
authors.lastname: Bittard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lascombe
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D060787:Neoplasm Grading; D047495:PPAR gamma / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D007004:Hypoglycemic Agents; D051034:Inhibitor of Apoptosis Proteins; D047495:PPAR gamma; D053218:Receptors, Death Domain; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C039671:ciglitazone