The carcinogen 2-acetylaminofluorene inhibits activation and nuclear accumulation of cyclin-dependent kinase 2 in growth-induced rat liver

Abstract

Growth arrest in G(1) is a common cellular response to DNA damage. In the present study, liver regeneration was combined with continuous exposure for 2-acetylaminofluorene (AAF) to study mechanisms of carcinogen-induced growth arrest in vivo. Growth arrest of uninitiated hepatocytes is central for AAF-induced promotion of premalignant lesions in rat liver. To characterize this growth arrest, we examined the activity of cyclin-dependent kinase (Cdk) 2 in unexposed liver and in AAF-exposed liver after growth induction by partial hepatectomy (PH). Rats were fed either a control diet or an AAF-supplemented diet. After 7 d, a two-third PH was performed and the animals were killed after 0, 12, 18, 24, and 36 h. Kinase assays showed that cyclin E- and Cdk2-associated activities were lower in AAF-exposed liver than in unexposed liver after PH. Although the total cellular levels of cyclin E and Cdk2 were similar, cyclin E-Cdk2 assembly was markedly reduced. In unexposed hepatocytes, Cdk2 translocated to the nuclei after PH. Much of the nuclear Cdk2 was in a rapidly migrating form, presumably representing the Thr160-phosphorylated form of Cdk2. In contrast, in AAF-exposed liver both nuclear Cdk2 accumulation and Thr160-phosphorylation of Cdk2 were reduced. Although p53 and p21(waf1/cip1) were induced by AAF, the binding of p21 to cyclin E and Cdk2 was not increased in growth arrested liver. In conclusion, hepatocyte growth arrest caused by AAF exposure was characterized by a lowered Cdk2 activity that was accompanied by a reduced assembly of cyclin E-Cdk2 complexes but not by binding of p21.

Hepatic iron overload in the portal tract predicts poor survival in hepatocellular carcinoma after curative resection

“…In rats, long‐term feeding of a carbonyl iron diet induced the proliferation of progenitor cells in the portal area, which eventually migrated into the central regions . As shown in animal studies, the degree of progenitor cell activation has been shown to be correlated with the severity of the underlying liver disease in patients . The progressive oxidative stress in the portal area due to portal iron overload may result in DNA damage, impaired regeneration, progenitor cell proliferation and evolution of cancer stem cells.…”

Improved Serum Alpha-Fetoprotein Levels after Iron Reduction Therapy in HCV Patients

“…Thus, the decrease in GGT observed in this study most likely reflects the improvement in hepatic iron-mediated oxidative stress with phlebotomy. Oxidative stress also inhibits the replication of mature hepatocytes, resulting in the activation of HPCs [ 42 , 43 ]. HPC accumulation is observed in diseased livers with enhanced hepatic oxidative stress, including livers with chronic hepatitis C [ 44 , 45 ].…”

Different growth capacity between infant and adult mouse hepatocytes in vitro correlates to the cyclin D1 level without relation to oxidative DNA damage

“…Infant animals are documented to be highly susceptible to chemically induced hepatic carcinogenesis (9). On the other hand, in adult animals, proliferating capacity of hepatocytes is markedly inhibited because of activation of checkpoint control after treatment with hepatic carcinogens (36, 37). The possibility that infant hepatocytes can proliferate even after suffering from DNA damage is of great interest in the context of high susceptibility to hepatic carcinogenesis.…”