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

Chae, Myung-Jong (Department of Internal Medicine, Kyung Hee University School of Medicine)
Shim, Jae-Jun (Department of Internal Medicine, Kyung Hee University School of Medicine)
Kim, Byung-Ho (Department of Internal Medicine, Kyung Hee University School of Medicine)
Hwangbo, Young (Department of Internal Medicine, Kyung Hee University School of Medicine)
Lee, Young-Ju (Department of Internal Medicine, Kyung Hee University School of Medicine)
Ha, Seung-Hyung (Department of Internal Medicine, Kyung Hee University School of Medicine)
Jang, Jae-Young (Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea)
Dong, Seok-Ho (Department of Internal Medicine, Kyung Hee University School of Medicine)
Kim, Hyo-Jong (Department of Internal Medicine, Kyung Hee University School of Medicine)
Chang, Young-Woo (Department of Internal Medicine, Kyung Hee University School of Medicine)
Chang, Rin (Department of Internal Medicine, Kyung Hee University School of Medicine)
Publication Information
The Korean Journal of Medicine / v.75, no.3, 2008 , pp. 288-299 More about this Journal
Abstract
Background/Aims: Thiazolidinediones, which are synthetic insulin sensitizers, are known activators of peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ ligands, including endogenous 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), are thought to elicit antineoplastic effects in various cancer cells. In this study, the antineoplastic effects of PPARγ 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 μM.. 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 PPARγ 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 PPARγ-independent pathway, is involved.
Keywords
Antineoplastic agents; Hepatocellular carcinoma; Peroxisome proliferator-activated receptor gamma;
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