Carcinogenesis, Vol 19, 299-304, Copyright © 1998 by Oxford University Press
JH Gill, NH James, RA Roberts and C Dive
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.
ARTICLES
The non-genotoxic hepatocarcinogen nafenopin suppresses rodent hepatocyte apoptosis induced by TGFbeta1, DNA damage and Fas
School of Biological Sciences, Manchester University, UK.
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