NF-κB: A Stress-Regulated Switch for Cell Survival

Nuclear factor-κB (NF-κB), a stress-regulated transcription factor belonging to the Rel family, has a pivotal role in the control of the inflammatory and the innate immune responses. Its activation rapidly induces the transcription of a variety of genes encoding cell adhesion molecules, inflammatory and chemotactic cytokines, cytokine receptors, and enzymes that produce inflammatory mediators. More recently, NF-κB activation has been connected with multiple aspects of oncogenesis, including the control of cell proliferation, migration, cell cycle progression, and apoptosis. Interestingly, NF-κB is constitutively activated in several types of cancer cells, including hematological and epithelial malignancies. In addition, activation of NF-κB in cancer cells by chemotherapy or radiation therapy has been associated with the acquisition of resistance to apoptosis, which has emerged as a significant impediment to effective cancer treatment. Selective cyclopentenone inhibitors of the IκB kinase, the key enzyme controlling NF-κB activation, were recently shown to be potent inducers of apoptosis in chemoresistant lymphoid malignancies. Increasing evidence, summarized in this review, indicates that the development of selective NF-κB inhibitors may represent a promising therapeutic tool to sensitize tumor cells to apoptosis and increase the efficacy of conventional anticancer drugs in a wide spectrum of malignancies.