Korean J Med.  2008 Sep;75(3):288-299.

Peroxisome proliferator-activated receptor gamma ligands exert antineoplastic effects in hepatocellular carcinoma cells

• Chae MJ
• Shim J
• Kim BH
• Hwangbo Y
• Lee YJ
• Ha SH
• Jang JY
• Dong SH
• Kim HJ
• Chang YW
• Chang R

Abstract

BACKGROUND/AIMS: Thiazolidinediones, which are synthetic insulin sensitizers, are known activators of peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma ligands, including endogenous 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), are thought to elicit antineoplastic effects in various cancer cells. In this study, the antineoplastic effects of PPARgamma ligands against hepatocellular carcinoma (HCC) cells were investigated.
METHODS
HepG2, Hep3B, and PLC/PRF5 cells were cultured with troglitazone (TGZ), pioglitazone (PGZ), rosiglitazone (RGZ), or 15d-PGJ2 at concentrations of 20-100 micrometer. Cell viability, cell cycle arrest, apoptosis, and caspase activity were measured using the MTT assay, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and colorimetric assays, respectively. The effects of various caspase inhibitors were also measured using a cell death detection ELISA.
RESULTS
All three cell lines expressed the PPARgamma gene. TGZ and 15d-PGJ2 strongly inhibited growth in HepG2, Hep3B, and PLC/PRF5 cells. In contrast, PGZ and RGZ showed a much weaker effect in all cell lines. In terms of cell cycle arrest and apoptosis, TGZ induced G0/G1 arrest in HepG2 cells and increased the apoptotic fraction in Hep3B and PLC/PRF5 cells. In contrast, 15d-PGJ2 induced apoptosis only in HepG2 and Hep3B cells. TGZ and 15d-PGJ2 increased caspase-3 activity significantly and increased caspase-9 activity slightly. TGZ- and 15d-PGJ2-induced apoptoses were inhibited by a pancaspase inhibitor (Z-VAD-FMK) and a caspase-3 specific inhibitor (Z-DEVD-FMK) in a dose-dependent manner.
CONCLUSIONS
TGZ and 15d-PGJ2 elicit antineoplastic effects in various HCC cells via caspase-dependent apoptotic induction. Their differential effects on similar cell types suggest that another antineoplastic mechanism, most likely a PPARgamma-independent pathway, is involved.

Keyword

Antineoplastic agents; Hepatocellular carcinoma; Peroxisome proliferator-activated receptor gamma

MeSH Terms

Antineoplastic Agents
Apoptosis
Carcinoma, Hepatocellular
Caspase 3
Caspase 9
Caspase Inhibitors
Cell Cycle Checkpoints
Cell Death
Cell Line
Cell Survival
Chromans
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Hep G2 Cells
Insulin
Ligands
Peroxisomes
PPAR gamma
Prostaglandin D2
Thiazolidinediones
Antineoplastic Agents
Caspase 3
Caspase 9
Caspase Inhibitors
Chromans
Insulin
Ligands
PPAR gamma
Prostaglandin D2
Thiazolidinediones