NF-κB addiction and its role in cancer: 'one size does not fit all'

Abstract

Activation of nuclear factor (NF)-κB, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of 'NF-κB addiction' in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, β-catenin, AR, GR and ER). As NF-κB is 'pre-active' in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus 'one size does not fit all' cancers.

Figure 1

Signaling network of NF-κB activation in cancer. Various pathways of NF-κB activation in cancers are shown. The sites of action of some phytochemicals are also indicated in the boxes. The network converges at three major sites (IKK kinase such as TAK1, IKK itself and the p50–p65 heterodimer). ASK1, apoptosis signal-regulating kinase 1; BAFF-R, TNF family member B cell-activating factor-receptor; CK II, casein kinase II; HTLV, human T-lymphotropic virus; LTβR, lymphotoxin-β receptor; MyD88, myeloid differentiation primary response gene 88; RalB, RAS-like protein B; RANK, receptor activator for nuclear factor κB; RIP, receptor interacting protein; Syk, spleen tyrosine kinase; TAK1, transforming growth factor (TGF)-β activating kinase 1; TBK, TRAF family member-associated NF-κB activator (TANK)-binding kinase; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor; TRADD, TNFR1-associated death domain; TRAF, TNF-receptor-associated factor; β-TrCP, β-transducin repeat-containing protein; TWEAK-R, TNF-related weak inducer of apoptosis-receptor; UV, ultra violet.

Figure 2

Sites of modification in p65 (RelA) subunit of NF-κB in cancer. Locations of various modification sites in the Rel homology domain and transactivation domains (TAD1 and 2) of p65 are shown. The possible effects are shown in the boxes. Ac, actylation; K, lysine residues; M, methylation; P, phosphorylation; S, serine residues; Ub, ubiquitination.

Figure 3

NF-κB interactions in cancer. NF-κB interacts with many transcription factors and transcriptional regulators. The interactions could be direct at the promoter, such as in AP1, HIF-1α, Notch1, JunD, CREB, SP1 or off the promoter, such as STAT3, p53 or both. The single-head arrow indicates activation, whereas the double-head arrow indicates direct and indirect activation. The blunt-end arrow indicates inhibition and negative regulation. For PPARs, see (Delerive et al., 1999; Chung et al., 2000; Planavila et al., 2005); for SIRT1 (Yeung et al., 2004); for Sir2 (Yang et al., 2007); for RXR (Na et al., 1999); for Daxx (Park et al., 2007); for GR (Ray and Prefontaine, 1994); for ER (Galien and Garcia, 1997); for SMRT (Lee et al., 2000); for Egr-1 (Chapman and Perkins, 2000); for HDACs (Ashburner et al., 2001; Liu et al., 2005); for PIAS (Chen et al., 2001); for FoxO4 (Zhou et al., 2009); for κB-ras (Tago et al., 2010); for β-catenin (Deng et al., 2002); for Egr-3 & 4 (Wieland et al., 2005); for TFIIB (Schmitz et al., 1995); for p300 (Morimoto et al., 2008); for BRCA1 (Benezra et al., 2003); for E2F1 (Lim et al., 2007); for IRF-1 (Sgarbanti et al., 2008); for SP-1 (Perkins et al., 1993); for C/EBPβ (Zwergal et al., 2006); for JunD (Toualbi-Abed et al., 2008); for Notch-1 (Cheng et al., 2001); for SRF (Franzoso et al., 1996); for HIF-1α (Scortegagna et al., 2008); for MEF2 (Kumar et al., 2005); for p53 (Jeong et al., 2004); for STAT3 (Yoshida et al., 2004; Yu and Kone, 2004); for AP-1 (Stein et al., 1993); for CDX2 (Kim et al., 2004); for PR (Kovalenko et al., 2003); and for AR (Palvimo et al., 1996).

Figure 4

Suppression of NF-kB activation by the Food and Drug Administration-approved drugs for cancer therapy. Molecular targets for many Food and Drug Administration-approved drugs for treatment of cancer are shown. Although these drugs act through their defined molecular targets, they inhibit NF-κB via pathway(s) that are not well defined. The X indicates an intermediate that could be either IKK or its upstream activators, which may be different for different pathways. EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor receptor; TNF, tumor necrosis factor; VEGFR, vascular endothelial cell growth factor receptor.