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Insights on distinct pathways of thiazolidinediones (PPARgamma ligand)-promoted apoptosis in TRAIL-sensitive or -resistant malignant urothelial cells.

PMID: 20099277 (view PubMed database entry)
DOI: 10.1002/ijc.25189 (read at publisher's website )

Marie Laure Plissonnier, Sylvie Fauconnet, Hugues Bittard, Isabelle Lascombe,

Thiazolidinediones, including rosiglitazone and troglitazone, are insulin-sensitizing drugs and high-affinity ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma). 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 PPARgamma 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.

Int. J. Cancer (International journal of cancer)
[2010, 127(8):1769-1784]

Cited: 12 times

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