Oltipraz promotion of liver regeneration after partial hepatectomy: The role of PI3-kinase-dependent C/EBPβ and cyclin E regulation

Abstract

Oltipraz, a representative cancer chemopreventive agent, regenerates cirrhotic liver via CCAAT/enhancer binding protein beta (C/EBPbeta). 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/EBPbeta-DNA binding activity in the liver of sham control rats and further enhanced PH-mediated nuclear translocation of C/EBPbeta. 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/EBPbeta and cyclin E were studied in H4IIE cells, a rat-derived hepatocyte cell line. Oltipraz potentiated the nuclear accumulation of C/ EBPbeta and C/EBPbeta-DNA binding activity in cells incubated in a medium containing serum. PI3K and its downstream kinase, p70S6 kinase, were both required for C/EBPbeta-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/EBPbeta and C/EBPbeta-dependent cyclin E expression via the PI3K-p70S6 kinase pathway.