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Research ArticleArticle

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Myung-Ae Bae and Byoung J. Song
Molecular Pharmacology February 2003, 63 (2) 401-408; DOI: https://doi.org/10.1124/mol.63.2.401
Myung-Ae Bae
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Byoung J. Song
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Abstract

The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non–insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time- and concentration-dependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 μM rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochromec, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys→Arg) or SEK1-KR (Lys→Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins.

Footnotes

  • Abbreviations:
    TRO
    troglitazone
    PPAR
    peroxisome proliferator-activated receptor
    RSG
    rosiglitazone
    ERK
    extracellular signal-regulated kinase
    JNK
    c-Jun N-terminal protein kinase
    p38 kinase
    p38 mitogen activated protein kinase
    MAP
    mitogen-activated protein
    DMSO
    dimethyl sulfoxide
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide
    ATF
    activator transcription factor
    wt
    wild type
    SEK
    stress activated protein kinase kinase
    JNK-KR
    c-Jun N-terminal protein kinase Lys→Arg mutant
    SEK1-KR
    stress activated protein kinase kinase 1 Lys→Arg mutant
    SP600125
    anthra[1,9-cd]pyrazol-6(2H)-one
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
    • Received May 24, 2002.
    • Accepted November 12, 2002.
  • U.S. Government
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Myung-Ae Bae and Byoung J. Song
Molecular Pharmacology February 1, 2003, 63 (2) 401-408; DOI: https://doi.org/10.1124/mol.63.2.401

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Research ArticleArticle

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Myung-Ae Bae and Byoung J. Song
Molecular Pharmacology February 1, 2003, 63 (2) 401-408; DOI: https://doi.org/10.1124/mol.63.2.401
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