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Vol. 63, Issue 2, 401-408, February 2003
Laboratory of Membrane Biochemistry and Biophysics, National
Institute on Alcohol Abuse and Alcoholism, National Institutes of
Health, Rockville, Maryland
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 cytochrome
c, 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 (LysArg), 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.
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