NF-kappaB Activation in Development and Progression of Cancer

Cancer Sci. 2007 Mar;98(3):268-74. doi: 10.1111/j.1349-7006.2007.00389.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Disease Progression
  • Humans
  • Models, Biological
  • NF-kappa B / metabolism*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Osteoclasts / metabolism
  • RANK Ligand / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • NF-kappa B
  • RANK Ligand
  • TNF Receptor-Associated Factor 6