While anticancer therapies aimed at particular pathways have mushroomed in recent years, one crucial target has remained elusive: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The pathway is constitutively active in the majority of cancers and provides a mechanistic link between chronic inflammation and tumorigenesis. As such, it represents an important target for anticancer therapy. The complex regulation of NF-κB activation has presented significant challenges for the development of such agents, but researchers are now beginning to better understand and embrace this complexity to drive development of a variety of novel NF-κB-targeting strategies.
The NF-κB Family
NF-κB was discovered in late 1980s as a nuclear factor that binds to the enhancer region of the kappa-light chain of immunoglobulin in B cells. It was subsequently shown to be a ubiquitous family of transcription factors that are present in all cells and control the transcription of more than 500 target genes involved in critical cellular pathways including proliferation and apoptosis. The NF-κB pathway is activated by a wide range of stimuli, including stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens.
In humans, there are five members of the NF-κB family: Rel-A, Rel-B, c-Rel, NF- κB-1, and NF-κB-2, which are able to form homo- and heterodimers with one another to produce a number of different NF-κB complexes with different activities. All family members share a Rel homology domain that is responsible for dimerization, nuclear translocation, DNA binding, and inhibition.
Under normal conditions, NF-κB is kept in an inactive state in the cytoplasm via the action of a family of inhibitors known as inhibitors of κB (IκBs), primarily IκBα. In response to an upstream stimulus, IκBα is phosphorylated by kinase enzymes, the IκB kinases (IKKs), and is subsequently targeted for degradation by the proteasomal pathway. Removal of IκBα inhibition releases the NF-κB complex, which is then free to migrate into the nucleus to initiate target gene expression.
About a decade ago it was discovered that there are in fact two NF-κB pathways with distinct mechanisms of regulation and nuclear targets. In the canonical pathway
, which is induced by a variety of stimuli, NF-κB is activated primarily by IKKβ, while in the noncanonical pathway
, which is induced by far fewer stimuli, NF-κB is activated primarily by IKKα, which in turn is activated by NF-κB-inducing kinase (IκBs). The two arms of NF-κB signaling have been shown to be equally important and are even interlinked in a number of ways.
NF-κB is activated by a number of upstream signaling pathways, including the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), platelet-derived growth factor receptor (PDGFR), and c-KIT pathways. Another key activator of NF-κB is the receptor-activator of NF-κB (RANK), which is a type of tumor necrosis factor (TNF) receptor. Further adding to the complex regulation of NF-κB signaling, it undergoes numerous posttranslational modifications, including methylation and acetylation, and it interacts with several other transcription factors, such as signal transducer and activator of transcription (STAT)-3 and hypoxia inducible factor (HIF)-1α, both of which regulate NF-κB activity.
The Many Roles of NF-κB
EBV, indicates Epstein-Barr virus; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV-8, human herpesvirus 8; HTLV, human T-lymphotropic virus; IL, interleukin; PDGFR, platelet-derived growth factor receptor; TNF, tumor necrosis factor.
Adapted from Sethi G, Sung B, Aggarwal BB. Nuclear factor-κB activation: from bench to bedside. Exp Biol Med. 2008; 233(1): 21-31.
Linking Inflammation and Cancer
The activation of NF-κB plays a role in the suppression of apoptosis, stimulation of proliferation, and promotion of migration and invasion, all of which are hallmarks of cancer. Unsurprisingly, therefore, NF-κB has been implicated in tumorigenesis. What is surprising is that oncogenic mutations in the NF-κB genes are rare and largely limited to lymphoid malignancies, yet NF-κB activation is observed in almost all tumors.
Several potential explanations have been offered for this phenomenon. For example, NF-κB activation is in part driven by mutational activation of upstream signaling pathways, which are frequently mutated in cancer.