Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643.
Wy-14,643 (WY) is a hypolipidemic drug that induces hepatic peroxisome proliferation and tumors in rodents. We previously showed that peroxisome proliferators increase NF-kappaB DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient in the p50 subunit of NF-kappaB had much lower cell proliferation in response to the peroxisome proliferator ciprofibrate. In this study we examined the promotion of hepatocarcinogenesis by WY in the p50 knockout (-/-) mice. The p50 -/- and wild type mice were first administered diethylnitrosamine (DEN) as an initiating agent. Mice were then fed a control diet or a diet containing 0.05% WY for 38 weeks. Wild-type mice receiving DEN only developed a low incidence of tumors, and the majority of wild-type mice receiving both DEN and WY developed tumors. However, no tumors were seen in any of the p50 -/- mice. Cell proliferation and apoptosis were measured in hepatocytes by BrdU labeling and the TUNEL assay, respectively. Treatment with DEN + WY increased both cell proliferation and apoptosis in both the wild-type and p50 -/- mice; DEN treatment alone has no effect. In the DEN/WY-treated mice, cell proliferation and apoptosis were slightly lower in the p50 -/- mice than in the wild-type mice. These data demonstrate that NF-kappaB is involved in the promotion of hepatic tumors by the peroxisome proliferator WY; however, the difference in tumor incidence could not be attributed to alterations in either cell proliferation or apoptosis.
Glauert
Howard P
HP
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40506, USA. hglauert@uky.edu
Eyigor
Aysegul
A
Tharappel
Job C
JC
Cooper
Simon
S
Lee
Eun Y
EY
Spear
Brett T
BT
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D020025:Peroxisome Proliferators / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*
D002273:Carcinogens; D052002:NF-kappa B p50 Subunit; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D004052:Diethylnitrosamine; C006253:pirinixic acid; D042962:Acyl-CoA Oxidase