Regulation of cell death and autophagy by IKK and NF‐κB: critical mechanisms in immune function and cancer

Summary: The cellular response to survive or to undergo death is fundamental to the benefit of the organism, and errors in this process can lead to autoimmunity and cancer. The transcription factor nuclear factor κB (NF‐κB) functions to block cell death through transcriptional induction of genes encoding anti‐apoptotic and antioxidant proteins. This is essential for survival of activated cells of the immune system and for cells undergoing a DNA damage response. In Ras‐transformed cells and tumors as well as other cancers, NF‐κB functions to suppress apoptosis—a hallmark of cancer. Critical prosurvival roles for inhibitor of NF‐κB kinase (IKK) family members, including IKKε and TBK1, have been reported, which are both NF‐κB‐dependent and ‐independent. While the roles of NF‐κB in promoting cell survival in lymphocytes and in cancers is relatively clear, evidence has been presented that NF‐κB can promote cell death in particular contexts. Recently, IKK was shown to play a critical role in the induction of autophagy, a metabolic response typically associated with cell survival but which can lead to cell death. This review provides an historical perspective, along with new findings, regarding the roles of the IKK and NF‐κB pathways in regulating cell survival.