title: The rodent non-genotoxic hepatocarcinogen nafenopin suppresses apoptosis preferentially in non-cycling hepatocytes but also elevates CDK4, a cell cycle progression factor.
abstract: Rodent non-genotoxic hepatocarcinogens such as nafenopin suppress spontaneous and transforming growth factor beta1 (TGFbeta1)-induced rat hepatocyte apoptosis as well as inducing DNA synthesis. We wished to determine if these two processes are associated. In primary rat hepatocytes, nafenopin suppressed apoptosis from 1.9 to 0.63% but more apoptotic bodies were bromodeoxyuridine (BrdU)-labelled (0.35%) than predicted statistically from a random distribution of apoptosis within the cycling and non-cycling populations (0.10%). In contrast, TGFbeta1 induced hepatocyte apoptosis (7.8%) but fewer hepatocytes were BrdU-labelled (0.29%) than predicted (0.82%). Western blot analyses showed that nafenopin and TGFbeta1 had opposing effects on cyclin-dependent kinase 4 (CDK4) protein: nafenopin elevated CDK4 compared with controls, whereas TGFbeta1 caused a reduction. These data suggest that non-genotoxic hepatocarcinogens suppress apoptosis in the non-cycling population of hepatocytes and elevate CDK4 levels, possibly allowing potentially tumourigenic cells to enter the cell cycle.
authors.affiliation: Molecular Pharmacology Group, School of Biological Sciences, Manchester University, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Gill
authors.forename: P
authors.initials: P
authors.lastname: Brickell
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.forename: R A
authors.initials: RA
authors.lastname: Roberts
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D009255:Nafenopin / Q000494:pharmacology*; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017208:Rats, Wistar; D016196:S Phase; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D020025:Peroxisome Proliferators; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D009255:Nafenopin; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases