The antidiabetic drug ciglitazone induces high grade bladder cancer cells apoptosis through the up-regulation of TRAIL.
PMID 22174792 · PloS one · 2011 · DOI 10.1371/journal.pone.0028354
Authors: Marie-Laure Plissonnier; Sylvie Fauconnet; Hugues Bittard; Isabelle Lascombe
Abstract
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. 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. Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.
Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; BH3 Interacting Domain Death Agonist Protein; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases; Cell Line, Tumor; Cell Membrane; Enzyme Activation; G2 Phase; Humans; Hypoglycemic Agents; Inhibitor of Apoptosis Proteins; Mice; Mitosis; Neoplasm Grading; PPAR gamma; Proteasome Endopeptidase Complex; Receptors, Death Domain; Signal Transduction; Survivin; TNF-Related Apoptosis-Inducing Ligand; Thiazolidinediones; Transcriptional Activation; Up-Regulation; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays
Cite
Marie-Laure Plissonnier; Sylvie Fauconnet; Hugues Bittard; Isabelle Lascombe. The antidiabetic drug ciglitazone induces high grade bladder cancer cells apoptosis through the up-regulation of TRAIL. PloS one (2011). PMID 22174792. DOI 10.1371/journal.pone.0028354.