Nuclear Factor-κB: A Holy Grail in Cancer Prevention and Therapy

Nuclear factor-κB (NF-κB) is a transcription factor that is activated in response to various inflammatory stimuli such as cytokines, growth factors, hormones, mitogens, carcinogens, chemotherapeutic agents, viral products, eukaryotic parasites, endotoxin, fatty acids, metals, radiation, hypoxia, and psychological, physical, oxidative, and chemical stresses. In addition, constitutively active NF-κB is frequently encountered in a wide variety of tumors, including breast, ovarian, colon, pancreatic, thyroid, prostate, lung, head and neck, bladder, and skin cancers; B-cell lymphoma; Hodgkin's disease; T-cell lymphoma; adult T-cell leukemia; acute lymphoblastic leukemia; multiple myeloma; chronic lymphocytic leukemia; and acute myelogenous leukemia. Furthermore, NF-κB activation has been shown to regulate the expression of over 400 genes involved in cellular transformation, proliferation, inflammation, viral replication, antiapoptosis, angiogenesis, invasion and metastasis, oxidative stress, and osteoclastogenesis. Therefore, because of the critical role NF- κB plays in the pathogenesis of cancer, specific inhibitors of this factor are being sought. Agents that prevent cancer or inflammation have been found to suppress NF-κB activation. Although IκBκ kinase is the major kinase, over 30 different protein kinases have been linked to the activation of NF-κB by different stimuli. The development of a drug that can specifically suppress NF-κB activation requires a full understanding of the mechanism by which NF-κB is activated in response to these various stimuli.