Peroxisome proliferator-activated receptor gamma ligands exert antineoplastic effects in hepatocellular carcinoma cells.
- Author:
Myung Jong CHAE
1
;
Jaejun SHIM
;
Byung Ho KIM
;
Young HWANGBO
;
Young Ju LEE
;
Seung Hyung HA
;
Jae Young JANG
;
Seok Ho DONG
;
Hyo Jong KIM
;
Young Woon CHANG
;
Rin CHANG
Author Information
1. Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea. kimbh@khu.ac.kr
- Publication Type:Original Article
- Keywords:
Antineoplastic agents;
Hepatocellular carcinoma;
Peroxisome proliferator-activated receptor gamma
- MeSH:
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
- From:Korean Journal of Medicine
2008;75(3):288-299
- CountryRepublic of Korea
- Language:Korean
-
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.
