Over-expression of protein kinase C delta is associated with a delay in preneoplastic lesion development in diethylnitrosamine-induced rat hepatocarcinogenesis.
The purpose of this study was to determine if decreasing dietary protein from 24% (high protein) to 5% casein (low protein), substituting sucrose and cornstarch isocalorifically for casein, would modify the activity of protein kinase C (PKC) alpha and beta isoenzymes, as well as the expression of PKC alpha, beta, delta and zeta subtypes in the particulate, soluble and nuclear fractions of rat liver, and the development of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the early stages (4, 7 and 60 days post-hepatectomy) of diethylnitrosamine-induced carcinogenesis promoted by 2-acetylaminofluorene in the diet plus partial hepatectomy (DEN-AAF-PH). In rats fed the 5% casein diet, body and liver weights decreased significantly compared with 24% casein-fed animals. However, the PKC total activity was unmodified. In 5% casein-fed rats, over-expression of PKC delta in the liver particulate fraction was detected at 7 and 60 days post-hepatectomy, with no significant PKC alpha and beta isoform activation. These animals showed only scattered GGT-positive hepatocytes at 60 days post-hepatectomy, with no appearance of hyperplastic foci or preneoplastic nodules. In contrast, rats fed the 24% casein diet demonstrated a progressive loss of PKC delta expression in the particulate fraction during tumour promotion, with activation and increased membrane association of PKC alpha and beta subtypes. These animals developed hyperplastic cell foci and preneoplastic nodules at 7 and 60 days respectively. Taken together, the results of this study suggest that overexpression of PKC delta in the liver particulate fraction of low protein-fed rats may play a specific role in inhibiting the development of hepatocellular focal lesions in the early stages of DEN-AAF-PH-induced carcinogenesis and confirm the role for nuclear PKC beta in promoting the selective growth of carcinogen-initiated hepatocytes in high protein-fed animals. No evidence for a role of PKC zeta in the carcinogenic process could be demonstrated.
La Porta
C A
CA
Department of General Physiology and Biochemistry, University of Milan, Italy.
Comolli
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R
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002364:Caseins; D004032:Diet; D004052:Diethylnitrosamine / Q000633:toxicity*; D006498:Hepatectomy; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000096:biosynthesis*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis
D002273:Carcinogens; D002364:Caseins; D007527:Isoenzymes; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D005723:gamma-Glutamyltransferase; D011493:Protein Kinase C