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KMID : 0043320090320040625
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Archives of Pharmacal Research
2009 Volume.32 No. 4 p.625 ~ p.635
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Oltipraz Promotion of Liver Regeneration after Partial Hepatectomy: The Role of PI3-kinase-Dependent C/EBPβ and Cyclin E Regulation
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Kim Sang-Geon
Kang Keon-Wook
Sung Dae-Ki
Cho Il-Je
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Abstract
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Oltipraz, a representative cancer chemopreventive agent, regenerates cirrhotic liver via CCAAT/enhancer binding protein β (C/EBPβ). This study examined the effect of oltipraz on liver regeneration after partial hepatectomy (PH) and explored the role of phosphatidylinositol 3-kinase (PI3K) pathway responsible in liver regeneration. Oltipraz treatment (30 mg/kg/day, for 3 days) promoted liver regeneration in PH rats, but did not increase hepatocyte growth factor production. Subcellular fractionation and electrophoretic mobility shift assays showed that oltipraz treatment increased C/EBPβ-DNA binding activity in the liver of sham control rats and further enhanced PH-mediated nuclear translocation of C/EBPβ. The expression of cyclin E and the activity of cyclin E-dependent kinase were both enhanced by oltipraz treatment of PH rats. The signaling pathway that controls C/EBPβ and cyclin E were studied in H4IIE cells, a rat-derived hepatocyte cell line. Oltipraz potentiated the nuclear accumulation of C/EBPβ and C/EBPβ-DNA binding activity in cells incubated in a medium containing serum. PI3K and its downstream kinase, p70S6 kinase, were both required for C/EBPβ-dependent induction of cyclin E by oltipraz, as shown by chemical inhibition and plasmid transfection experiments. The results of this study demonstrate that oltipraz treatment enhances liver regeneration after PH, which involves activation of C/EBPβ and C/EBPβ?dependent cyclin E expression via the PI3K-p70S6 kinase pathway.
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KEYWORD
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Oltipraz, Liver Regeneration, PI3-kinase, C/EBPβ, Cyclin E
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