er homeostasis in response to various environmental challenges that can induce the AT7867 AT-7867 production of TNF and other hepatotoxic cytokines. The activated IKK/NF ?B pathway may play a tumor promoting role by protecting tumor cells from death or enhancing their proliferation. This hypothesis was first tested in a mouse model of azoxymethane dextrane sulfate sodium induced colitisassociated cancer. Conditional disruption of the Ikk gene in intestinal epithelial cells resulted in increased apoptotic elimination of AOM induced premalignant cells and greatly reduced the development of colonic adenomas. However, strikingly different results were obtained in the diethylnitrosamine induced mouse HCC model. DEN is a pro carcinogen that, upon metabolic activation in zone 3 hepatocytes, forms bulky DNA adducts.
Upon subsequent cell proliferation, some of these DNA adducts are fixed into permanent genetic alterations that may cause activation of oncogenes, such as catenin. A single dose of DEN given to two weekold mice is sufficient to induce HCC in 100% of male mice. However, when DEN is given to BI6727 male mice that are older than 4 weeks of age, it is no longer effective in HCC induction on its own and requires assistance from other tumor promoters, such as phenobarbitol. This agedependent difference in carcinogenic efficacy is not likely to be due to altered metabolic activation of DEN. The main reason that DEN is not a complete carcinogen in mice that are more than 4 weeks old is the nearly complete absence of proliferating hepatocytes. Thus, any agent that induces hepatocyte proliferation should function as a tumor promoter.
Indeed, partial hepatectomy after DEN administration results in effective hepatocarcinogenesis in older mice. It was found that liver specific disruption of IKK greatly enhances DEN induced hepatocyte death relative to wild type mice. Although this may enhance the elimination of DEN damaged hepatocytes, it should be noted that enhanced hepatocyte death also results in enhanced compensatory proliferation. Consequently, Ikk?hep mice are 3 4 fold more susceptible to DEN induced HCC development than wild type mice. An even more striking effect on HCC development is seen upon the conditional deletion of hepatocyte IKK?/NEMO. In this case, Ikk??hep mice exhibit spontaneous liver damage and sequentially develop hepatosteatosis, hepatitis, liver fibrosis, and HCC without any known exposure to a carcinogen.
Multiple mechanisms were proposed to explain the pro survival function of the IKK/NF ?B pathway, which can either enhance tumor development or attenuate tumor development. In the liver a critical pro survival mechanism involves NF ?B,s ability to maintain anti oxidant defenses by controlling the expression of several key reactive oxygen species scavenging proteins. Mice that lack IKK exhibit extensive ROS accumulation in their livers shortly after injection of DEN, whose metabolism in zone 3 hepatocytes results in ROS production. Increased ROS accumulation is also seen in livers of unchallenged Ikk??hep mice. ROS accumulation in the liver can be prevented by dietary administration of the potent anti oxidant butylated hydroxyanisole. Indeed, liver damage, compensatory proliferation and hepatocarcinogenesis in both Ikk?hep and Ikk?