Insights on distinct pathways of thiazolidinediones (PPARγ ligand)‐promoted apoptosis in TRAIL‐sensitive or ‐resistant malignant urothelial cells

Thiazolidinediones, including rosiglitazone and troglitazone, are insulin‐sensitizing drugs and high‐affinity ligands for the peroxisome proliferator‐activated receptor γ (PPARγ). Apart from their antidiabetic activity, these molecules possess antitumor properties. We investigated their potential apoptotic effects on RT4 (derived from a well‐differentiated Grade I papillary tumor) and T24 (derived from an undifferentiated Grade III carcinoma) bladder cancer cells. Rosiglitazone induced G2/M or G0/G1 phase cell cycle arrest in RT4 and T24 cells, respectively. Only troglitazone triggered apoptosis via extrinsic and intrinsic pathways in both cell lines. Interestingly, rosiglitazone amplified TRAIL‐induced apoptosis in TRAIL‐sensitive RT4 cells or let TRAIL‐resistant T24 cells to respond to TRAIL. Thiazolidinediones acted through PPARγ activation‐independent mechanisms. The underlying mechanisms involved for the first time in cancer cells the upregulation of soluble and/or membrane‐bound TRAIL. This was associated with increased cell surface death receptor 5 expression and c‐FLIP and survivin downregulation, mediated in part through proteasome‐dependent degradation in troglitazone‐promoted cell death. Therefore, the combination of rosiglitazone and TRAIL could be clinically relevant as chemopreventive or therapeutic agents for the treatment of TRAIL‐resistant high‐grade urothelial cancers.