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

The role of NF-kappa B activation in tumor initiation has not been thoroughly investigated. We generated Ikk beta(EE)(IEC) transgenic mice expressing constitutively active I kappa B kinase beta (IKK beta) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikk beta(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, Ikk beta(EE)(IEC) mice exhibited more beta-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/Delta IEC) mice, and their survival was severely compromised. IEC of Ikk beta(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 Ikk beta(EE)(IEC)/Apc(+/Delta IEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early beta-catenin(+) lesions and tumor load. The results suggest that persistent NF-kappa B activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.