Chronic epithelial NF-kappaB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation

The role of NF-kappaB activation in tumor initiation has not been thoroughly investigated. We generated Ikkbeta(EE)(IEC) transgenic mice expressing constitutively active IkappaB kinase beta (IKKbeta) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkbeta(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkbeta(EE)(IEC) mice exhibited more beta-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/DeltaIEC) mice, and their survival was severely compromised. IEC of Ikkbeta(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkbeta(EE)(IEC)/Apc(+/DeltaIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early beta-catenin(+) lesions and tumor load. The results suggest that persistent NF-kappaB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage