Over-expression of protein kinase C ? is associated with a delay in preneoplastic lesion development in diethylnitrosamine-induced rat hepatocarcinogenesis

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Abstract
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) α and β isoenzymes, as well as the expression of PKC α, β, δ and ζ subtypes in the particulate, soluble and nuclear fractions of rat liver, and the development of γ-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 δ in the liver particulate fraction was detected at 7 and 60 days post-hepatectomy, with no significant PKC α and β 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 δ expression in the particulate fraction during tumour promotion, with activation and increased membrane association of PKC α and β 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 δ 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 β in promoting the selective growth of carcinogen-initiated hepatocytes in high proteinfed animals. No evidence for a role of PKC ζ in the carcinogenic process could be demonstrated

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