Low p38 MAPK and JNK activation in cultured hepatocytes of DRH rats; a strain highly resistant to hepatocarcinogenesis.
DRH rats are a hepatocarcinogenesis-resistant strain isolated from hepatocarcinogenesis-sensitive Donryu rats, and the liver of DRH shows less histological damage and fewer/smaller neoplastic hepatic lesions by the treatment with hepatocarcinogens. To investigate the mechanism of the resistance, the properties of hepatocytes of DRH and Donryu were compared. In primary culture, DRH hepatocytes exhibited higher proliferation and less apoptosis than Donryu hepatocytes in the presence of EGF and insulin. However, such difference was not correlated to the degree of DNA damage associated with cell culture or cell cycle checkpoint function. Although the mitogen-activated protein kinases [EGF receptor (EGFR) and extracellular signal regulating kinases (ERK1/2)] were activated to the same degree, the stress-activated protein kinases [p38 mitogen-activated protein kinase (p38) and c-jun N-terminal kinase (JNK)] were activated to a lesser degree in the DRH hepatocytes. Treatment with 2-acetylaminofluorene (2-AAF) in vivo also resulted in less JNK and p38 activation in the DRH livers. Furthermore, apoptosis signal-regulating kinase 1 (ASK1) was inhibited by the lysate from the DRH but not by the Donryu hepatocytes. The low activation of the stress-activated protein kinases may be linked to the resistance to cellular stress, which may underlie the hepatocarcinogenesis-resistance in DRH rats.
Honmo
Satoshi
S
Department of Pathology, Asahikawa Medical College, East, Midorigaoka, Asahikawa, Japan.
Ozaki
Atsuko
A
Yamamoto
Masahiro
M
Hashimoto
Norikazu
N
Miyakoshi
Masaaki
M
Tanaka
Hiroki
H
Yoshie
Masumi
M
Tamakawa
Susumu
S
Tokusashi
Yoshihiko
Y
Yaginuma
Yuji
Y
Kasai
Shinichi
S
Ogawa
Katsuhiro
K
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002273:Carcinogens; D015073:2-Acetylaminofluorene; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5