Dietary antioxidants have been shown to inhibit carcinogenesis in many studies, but the mechanisms by which they do so are unclear. One possibility is that they influence the activation of oxidative stress-sensitive transcription factors, such as NF-kB. NF-kB has been found to be activated by hepatic tumor-promoting agents such as PCBs, phenobarbital, and peroxisome proliferators; the activation by peroxisome proliferators has been found to be mediated, at least in part, by active oxygen. The antioxidant vitamin E inhibits NF-kB activation by peroxisome proliferators, both in vivo and in vitro. Whether the ability of vitamin E to inhibit NF-kB activation is responsible for its anti-carcinogenic effect is unclear, however. The development of a knockout mouse model that is deficient in the p50 subunit of NF-kB will allow the investigators to answer this question. They have found that the cell proliferation-inducing effects of peroxisome proliferators are decreased in this model. In this project, the investigators propose to test the hypothesis that vitamin E and other antioxidants exert their anti- carcinogenic effects at least in part by inhibiting NF-kB activation. The investigators will use the p50 knockout mice to examine if vitamin E-induced changes in hepatic cell proliferation, apoptosis, antioxidant status, and gene expression are mediated by NF-kB. They will then determine if effects on tumor promotion are mediated by NF-kB. These studies will show if the inhibition of NF-kB activation is necessary for the anti-carcinogenic effects of vitamin E and other antioxidants. These results will provide a mechanistic basis for possible dietary recommendations to prevent cancer.
| Li, Jun; Harp, Casey; Tharappel, Job C et al. (2011) Effect of vitamin E on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-?B after treatment with phenobarbital. Food Chem Toxicol 49:2706-9 |
| Tharappel, Job C; Spear, Brett T; Glauert, Howard P (2008) Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kappaB. Toxicol Appl Pharmacol 226:338-44 |
| Calfee-Mason, Karen G; Lee, Eun Y; Spear, Brett T et al. (2008) Role of the p50 subunit of NF-kappaB in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate. Food Chem Toxicol 46:2062-73 |
