Sensitization of tumor cells to cancer therapy by molecularly targeted inhibition of the inhibitor of nuclear factor κB kinase
The inhibitor of nuclear factor κB kinase (IKK)-nuclear factor κB (NFκB) pathway is one ofthe most important cellular signal transduction pathways. It can be activated by diverse stimuli, resulting inliberation of cytoplasmic NFκB from inhibition by inhibitors of NFκB (IκB) after IκB are phosphorylatedby IKKβ and IKKα via the canonical and non-canonical pathways, respectively. Activated NFκB thentranslocates into the nucleus to regulate various NFκB target genes. Through regulation of its target genes,NFκB can regulate various physiologic processes such as cell proliferation, migration and survival. Moreimportantly, activation of the IKK-NFκB pathway has been implicated in carcinogenesis, tumor development,progression and metastasis, and cancer resistance to radiotherapy and chemotherapy. Therefore, molecularlytargeted inhibition of the different components of this pathway has been widely explored for treatment ofcancer either alone or in combination with other cancer therapies. A growing body of evidence suggests thatIKKβ may be a better cancer treatment target in this pathway, because several novel NFκB-independentfunctions of IKKβ have been identified recently, including promotion of DNA double strand break repair toincrease tumor cell resistance to ionizing radiation and chemotherapy in an apoptosis-independent manner.In this review, we highlight some of these new findings and discuss the therapeutic potential of IKKβ specificinhibitors as a novel tumor sensitizer.