Fig. 1

Regulation of NF-κB activation by cellular signaling molecules. Upon stimulation of cells, activation of protein kinases such as phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), c-Jun NH₂-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) induce phosphorylation of IKKα/β. IκBα is rapidly phosphorylated by IKKα/β and degraded via the ubiquitin-proteasome pathway. The resulting free NF-κB dimer (p50-p65) translocates to the nucleus for the transcriptional regulation of multiple target genes. Some of the aforementioned proteine kinases may also catalyze the phosphorylation of p65 subunit of NF-κB, facilitating the nuclear translocation and/or interaction with the coactivator CBP/p300. Chemopreventive phytochemicals can inhibit phosphorylation and/or ubiquitination of IκBα or phosphorylation of p65 induced by several oncogenic stimuli, thereby hampering the nuclear translocation and DNA binding of NF-κB. The cysteine residues present in IKKα/β are critical for catalytic activity and can be oxidized by prooxidants or covalent modified by electrophiles, leading to inactivation of the enzyme. Some dietary phytochemicals or their metabolites can act as prooxidants capable of directly oxidizing cysteine thiol or indirectly by altering cellular redox status and subsequently releasing ROS. Other groups of chemopreventive phytochemicals, especially those capable of acting as Michael reaction acceptors, are electrophilic per se and can hence directly modify the cysteine residues of IKK. Similar thiol modification by electrophilic phytochemicals was also found to occur for the p50 subunit of NF-κB [30], but this event is not included in this illustration to avoid complexity