The Antidiabetic Drug Ciglitazone Induces High Grade Bladder Cancer Cells Apoptosis through the Up-Regulation of TRAIL

International audienceBACKGROUND: 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

Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma

Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC

miR-122-regulated metabolic circuits: micro-management of lipid metabolism in the human liver

International audienc

Implication de TRAIL dans l'induction de l'apoptose par les thiazolidinediones, agents antidiabétiques, ligands de PPARy (étude dans deux modèles de carcinogenèse épithéliale)

BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

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

International audienceThiazolidinediones, 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

Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma

Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC

Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma

Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC

Ciglitazone induces apoptosis in T24 cells.

<p>Cells were exposed for 24 h to vehicle or ciglitazone at the indicated concentrations. (A) The percentage of cells showing the hypodiploid DNA content (sub-G1 peak) was evaluated by flow cytometry analysis. (B), (C) The cleavage of caspases 9, 8, 3 and PARP as well as the expression of pro- and anti-apoptotic proteins were determined by western blotting analysis. (D, <i>left</i>) Cells were preincubated 1 h with 50 µM caspase 8 (Z-IETD-FMK) or 9 (Z-LEHD-FMK) specific inhibitor before treatment with 40 µM ciglitazone for 12 h and assessment of caspases 8, 9, 3 and Bid processing was analysed by western-blotting. β-actin was used as an internal loading control ; (D, <i>right</i>) After indicated treatments, cells were stained with PI for DNA fragmentation analysis by flow cytometry. Data are means ± SD of 3 independent experiments performed in triplicates. *<i>P</i><0.05, significant differences compared with untreated cells ; **<i>P</i><0.05, significant differences compared with ciglitazone-treated cells with the use of two-tailed unpaired Student's <i>t</i> test.</p