The non-genotoxic hepatocarcinogen nafenopin suppresses rodent hepatocyte apoptosis induced by TGFbeta1, DNA damage and Fas.
The suppression of apoptosis may contribute to the carcinogenicity of the peroxisome proliferators (PPs), a class of non-genotoxic rodent hepatocarcinogens. Our previous work demonstrated that the PP nafenopin suppressed both spontaneous and transforming growth factor beta1 (TGFbeta1)-induced hepatocyte apoptosis both in vivo and in vitro. Here, we extend these observations by demonstrating the ability of nafenopin to suppress apoptosis induced by other major candidates for the signalling of cell death in the liver. Treatment of rat or mouse hepatocyte monolayers with TGFbeta1 or the DNA damaging drugs etoposide or hydroxyurea induced high levels of apoptosis. Western blot analysis did not support a role for either p53 or p21waf1 in etoposide-induced apoptosis in rat hepatocytes. Treatment of mouse hepatocytes with an agonistic anti-Fas antibody also resulted in an induction of high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all three stimuli. Overall, our studies demonstrate that the ability of nafenopin to protect hepatocytes from apoptosis is not restricted to species or apoptotic stimulus. It is possible, therefore, that the PPs may suppress apoptosis by acting on diverse signalling pathways. However, it seems more likely that nafenopin suppresses hepatocyte apoptosis elicited by each death stimulus by impinging on a core apoptotic mechanism.
Gill
J H
JH
School of Biological Sciences, Manchester University, UK.
James
N H
NH
Roberts
R A
RA
Dive
C
C
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004306:Dose-Response Relationship, Immunologic; D064429:Fatty Acid Synthases / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009255:Nafenopin / Q000494:pharmacology*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D002273:Carcinogens; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D009255:Nafenopin; D064429:Fatty Acid Synthases