15-Deoxy-Δ-12-14-PGJ2 Regulates Apoptosis Induction and Nuclear Factor-κB Activation Via a Peroxisome Proliferator-Activated Receptor-γ–Independent Mechanism in Hepatocellular Carcinoma

Abstract

The peroxisome proliferator-activated receptor-γ (PPARγ) high-affinity ligand, 15-deoxy-Δ-12,14-PGJ2 (15d-PGJ2), is toxic to malignant cells through cell cycle arrest and apoptosis induction. In this study, we investigated the effects of 15d-PGJ2 on apoptosis induction and expression of apoptosis-related proteins in hepatocellular carcinoma (HCC) cells. 15d-PGJ2 induced apoptosis in SK-Hep1 and HepG2 cells at a 50 μm concentration. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (2-VAD-fmk), only partially blocked apoptosis induced by 40 μm 15d-PGJ2. This indicated that 15d-PGJ2 induction of apoptosis was associated with a caspase-3–independent pathway. 15d-PGJ2 also induced down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bclx, and apoptotic protease-activating factor-1 in SK-Hep1 cells but not in HepG2 cells. However, 15d-PGJ2 sensitized both HCC cell lines to TNF-related apoptosis-induced ligand–induced apoptosis. In SK-Hep1 cells, cell toxicity, nuclear factor-κB (NF-κB) suppression, and XIAP down-regulation were induced by 15d-PGJ2 treatment under conditions in which PPARγ was down-regulated. These results suggest that the effect of 15d-PGJ2 was through a PPARγ-independent mechanism. Although cell toxicity was induced when PPARγ was down-regulated in HepG2 cells, NF-κB suppression and XIAP down-regulation were not induced. In conclusion, 15d-PGJ2 induces apoptosis of HCC cell lines via caspase-dependent and -independent pathways. In SK-Hep1 cells, the ability of 15d-PGJ2 to induce cell toxicity, NF-κB suppression, or XIAP down-regulation seemed to occur via a PPARγ-independent mechanism, but in HepG2 cells, NF-κB suppression by 15d-PGJ2 was dependent on PPARγ.