15-deoxy-delta-12-14-PGJ2 regulates apoptosis induction and nuclear factor-kappaB activation via a peroxisome proliferator-activated receptor-gamma-independent mechanism in hepatocellular carcinoma.

Abstract

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

• Authors: Hiroshi Okano, Katsuya Shiraki, Hidekazu Inoue, Yutaka Yamanaka, Tomoyuki Kawakita, Yukiko Saitou, Yumi Yamaguchi, Naoyuki Enokimura, Norihiko Yamamoto, Kazushi Sugimoto, Kazumoto Murata, Takeshi Nakano
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 83 Issue 10 Pg. 1529-39 (Oct 2003) ISSN: 0023-6837 [Print] United States
• PMID: 14563954 (Publication Type: Journal Article)

Chemical References

• 15-deoxy-delta(12,14)-prostaglandin J2
• Apoptosis Regulatory Proteins
• Membrane Glycoproteins
• NF-kappa B
• Receptors, Cytoplasmic and Nuclear
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Transcription Factors
• Tumor Necrosis Factor-alpha
• CASP3 protein, human
• Caspase 3
• Caspases
• Prostaglandin D2

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Blotting, Western
• Carcinoma, Hepatocellular (metabolism, pathology)
• Caspase 3
• Caspases (metabolism)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation
• Humans
• Liver Neoplasms (metabolism, pathology)
• Membrane Glycoproteins (pharmacology)
• NF-kappa B (biosynthesis)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• TNF-Related Apoptosis-Inducing Ligand
• Transcription Factors (metabolism)
• Transfection
• Tumor Cells, Cultured (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)