Pigment Epithelial-derived Factor Inhibits c-FLIP Expression and Assists Ciglitazone-induced Apoptosis in Hepatocellular Carcinoma

Background: Pigment epithelial-derived factor (PEDF) displays its antiangiogenicity by mechanisms partly involving suppression of the cellular FADD-like IL-1 beta-converting enzyme (FLICE)/caspase-8-inhibitory protein (c-FLIP) expression in endothelial cells. c-Jun NH2-terminal kinases (JNKs) regulate c-FLIP expression in endothelial cells. The effect of PEDF on other cells remains unclear. Materials and Methods: c-FLIP expression was assessed by semi-quantitative reverse transcriptase (RT)-PCR and immunoblotting. Pharmacological inhibitors were used to examine the involvement of PEDF signaling. Results: PEDF can also down-regulate c-FLIP expression in hepatoma cell line SK-Hep-1. PEDF induced p38 kinase phosphorylation in SK-Hep-1 cells. The effect of PEDF on c-FLIP expression was attenuated by p38 kinase inhibitor, but not JNK inhibitor. In addition, PEDF pretreatment significantly increased the sensitivity of SK-Hep-1 cells to procaspase-8 cleavage and apoptosis induced by ciglitazone. Conclusion: PEDF-induced p38 signaling causes c-FLIP down-regulation in SK-Hep-1. We postulate PEDF has a novel effect on apoptotic inducible activity in hepatoma cells.