NF-κB was first described as a B-cell-specific transcription factor that binds the κB site in the immunoglobulin (Ig) κ light chain enhancer region. However, it is now known that NF-κB has multiple critical roles in the regulation of immune responses and influences gene expression events that impact cell survival, differentiation, and proliferation. The family of NF-κB proteins consists of five members, p50 (p105), p52 (p100), p65 (RelA), c-Rel, and RelB, encoded by the genes NF-κB1, NF-κB2, RELA, REL, and RELB, respectively. All these molecules share an N-terminal Rel homology domain (RHD) that is responsible for DNA binding and homo- and hetero-dimerization [1,2].

NF-κB dimers bind to κB sites within the promoters/enhancers of target genes and regulate transcription through the recruitment of co-activators and co-repressors. The transcription activation domain (TAD) necessary for the positive regulation of gene expression is present only in p65, c-Rel, and RelB. Because p50 and p52 lack TADs, they can repress transcription unless associated with a TAD-containing NF-κB family member or other proteins capable of co-activator recruitment [1] Constitutive binding of p50 or p52 homodimers to κB sites on NF-κB-responsive promoters may thus act to check NF-κB transactivation until displaced by transcriptionally competent NF-κB dimers.

In unchallenged cells NF-κB dimers are bound to inhibitory IκB proteins retaining them in the cytoplasm. Two major pathways lead to translocation of NF-κB dimers from the cytoplasm to the nucleus: the canonical pathway and the alternative pathway (Figure 1). The canonical NF-κB pathway is triggered by pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs) that engage different receptors belonging to the TNF receptor (TNFR), IL-1 receptor (IL-1R) or Toll-like receptor (TLR) superfamilies. Via various adaptor molecules signaling impinges on the IκB kinase (IKK) complex, which acts as the central regulator of NF-κB activation. The IKK complex is comprised of two catalytical subunits IKKα (IKK1 or CHUK) and IKKβ (IKK2) as well as the regulatory subunit IKKγ (NEMO). In case of the canonical pathway, the activated IKK complex phosphorylates IκBs in an IKKβ/IKKγ dependent manner. These phosphorylated IκBs are now subject to poly-ubiquitination and consecutive proteasomal degradation, thus liberating p50/p65 heterodimers that can now translocate to the nucleus to initiate transcription of genes that are involved in cell survival, immunity and inflammation, cell proliferation and cell migration. Furthermore, activated p50/65 dimers activate genes encoding chemokines, cytokine and adhesion molecules that are important for innate immune response to invading microorganisms and are required for migration of inflammatory and phagocytic cells to tissues where NF-κB has been activated in response to infection or injury [2,3]. NF-κB dimers also assure the re-synthesis of IκB proteins that serve as negative feedback inhibitors. In contrast, the alternative NF-κB pathway is triggered by different TNF superfamily members such as BAFF, lymphotoxin-β or CD40L. These agonists induce processing of p100 to p52 via activation of IKKα, resulting in the nuclear translocation of p52-RelB. The alternative pathway has been suggested to play a central role in development and maintenance of secondary lymphoid organs. The canonical NF-κB pathway may also be indirectly linked to the alternative NF-κB pathway and may influence the amplitude and duration of its activation [2,4-6]. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas.

NF-κB is persistently activated in several types of hematological and solid malignancies [7,8]. While only recently loss of function mutations in NFKBIA have been described in glioblastoma patients [9], most sporadically occurring solid tumors do not harbor any mutations in genes encoding key members of this pathway. In contrast, in various lymphoid malignancies chromosomal translocations, amplifications, deletions and mutations effecting genes coding for NF-κB and IκB proteins can result in constitutive NF-κB activity [10]. In the absence of activating mutations, the canonical NF-κB pathway is commonly activated by an autocrine or paracrine cytokine secretion in solid tumors. Persistent NF-κB signaling within the tumor microenvironment confers enhanced tumor cell survival and proliferation as well as stimulation of invasive growth [11]. Moreover, chronic inflammation that has been shown to increase the risk of various malignancies [12] is invariably associated with the activation of NF-κB and its effector pathways. Therefore, NF-κB has been suggested to be the missing link between these two processes. In the following sections we will review evidence demonstrating the various NF-κB controlled mechanisms with a special focus on the pathogenesis of different gastrointestinal tumors.

NF-κB is constitutively activated in a large variety of human tumors. Recent mouse genetic studies have helped to unravel the diverse molecular mechanisms of this transcription factor in different cell types and have provided strong evidence that pharmacological inhibition of this signaling cascade may be an attractive novel strategy for the treatment of inflammation associated gastrointestinal tumors but also for a large variety of other tumors [10]. Although under certain circumstances, a cell type specific inhibition of NF-κB may for example increase the risk of HCC development, it is unlikely that pharmacological IKKβ inhibitors may have the same effects considering that such compounds would not target only hepatocytes, but would block NF-κB activation in inflammatory cells as well. Whether such specific IKKβ inhibitors however will be successful as single agents needs to be evaluated. Nevertheless, due to the potential of NF-κB inhibitors to increase sensitivity to chemotherapeutic drugs and irradiation based on studies performed in xenograft models [28], combination therapies may represent an excellent strategy for the therapy of advanced cancer stages and may allow the administration of lower doses of cytotoxic drugs, which could also decrease the unwanted side effects of such substances. Importantly, due to the great impact on cells of the B and T cell lineage [29] long-term IKKβ inhibition can cause loss of adaptive immunity. Moreover, NF-κB's recently described role in negatively regulating IL-1β processing that is also causally involved in the pathogenesis of granulocytosis [30,31], could also enhance susceptibility to develop septic shock upon bacterial infections in patients that use IKKβ inhibitors over extended time periods or at high doses. Thus, the usage of specific IKKβ inhibitors as cancer preventive agents may be restricted to cancer therapy either alone or in combination with cytotoxic drugs. In any case the effects on the immune system have to be monitored very closely.

Considering the promising data obtained from various tumor studies in genetically engineered mice, it will be essential to explore whether such novel IKKβ inhibitory molecules that are currently being developed will prove to be efficacious anti-carcinogenic compounds for the treatment of human cancer patients. Exciting times are lying ahead of us when we will determine whether the preclinical results will hold their promise once translated into the clinics.