NF-kappaB activation in development and progression of cancer.

Nuclear factor-kappaBeta (NF-kappaB) binds specifically to NF-kappaB-binding sites (kappaB sites, 5'-GGGRNNYYCC-3'; R, purine; Y, pyrimidine; N, any nucleotide) present in enhancer regions of various genes. Binding of various cytokines, growth factors and pathogen-associated molecular patterns to specific receptors activates NF-kappaB and expression of genes that play critical roles in inflammation, innate and acquired immunity, bone remodeling and generation of skin appendices. Activation of NF-kappaB is also involved in cancer development and progression. NF-kappaB is activated in cells that become malignant tumors and in cells that are recruited to and constitute the tumor microenvironment. In the latter scenario, the TLR-TRAF6-NF-kB pathways seem to play major roles, and NF-kappaB activation results in production of cytokines, which in turn induce NF-kappaB activation in premalignant cells, leading to expression of genes involved abnormal growth and malignancy. Furthermore, NF-kappaB activation is involved in bone metastasis. Osteoclasts, whose generation requires the RANK-TRAF6-NF-kappaB pathways, release various growth factors stored in bone, which results in creation of microenvironment suitable for proliferation and colonization of cancer cells. Therefore, NF-kappaB and molecules involved its activation, such as TRAF6, are attractive targets for therapeutic strategies against cancer.