Oltipraz promotion of liver regeneration after partial hepatectomy: The role of PI3-kinase-dependent C/EBPbeta and cyclin E regulation.
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.
Cho
Il Je
IJ
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea.
Sung
Dae Ki
DK
Kang
Keon Wook
KW
Kim
Sang Geon
SG
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D019927:Cyclin E / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors; D014162:Transfection
D022782:CCAAT-Enhancer-Binding Protein-beta; D019927:Cyclin E; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D011719:Pyrazines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz