NF-κB in cancer - A friend turned foe

The nuclear factor of κB (NF-κB) family of heterodimeric transcription factors plays an instrumental role in immune, inflammatory, and stress responses. NF-κB induces the expression of diverse target genes that promote cell cycle progression, regulate apoptosis, and facilitate cell adhesion, angiogenesis, and metastasis. Given the ability of NF-κB to influence these cardinal features of neoplastic transformation, it is no surprise that tumor cells of almost every tissue type acquire the ability to constitutively activate NF-κB via a host of diverse genetic alterations and viral proteins. The activation of NF-κB not only enables malignant transformation and tumor progression, but also provides a mechanism by which tumor cells escape immune surveillance and resist therapy. NF-κB may be inhibited by targeting either the apical signaling proteins responsible for its activation in specific types of cancer, the downstream kinases (IκB kinase and casein kinase 2) at which NF-κB-activating signaling pathways converge, the proteasome-mediated degradation of the inhibitor of κB (IκB) proteins, or the transcriptional activity of Re1 proteins. Since NF-κB inhibitors can sensitize tumor cells to apoptosis signaling pathways activated by death receptors, interferons, and immune effector cells, they hold enormous promise for the development of effective combinatorial regimens against a wide spectrum of hematologic and epithelial malignancies.