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 ‘preactive’ 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.

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

“…15 Here, we also confirm previous data that tumor MS express higher levels of IL6 compared with normal ones 7 and that the expression of the cytokine correlates with that of the Notch3/Jagged1 stem cell regulatory axis. 6,7,34 SLUG, an NF-kB controlled pivot of the stem cell phenotype, 9,10 also takes part to such a regulatory activity of NRs agonists.…”

“…Overall, the data here presented sustain the notion that the NF-kB inhibition 8,[13][14][15] may constitute a suitable strategy to target CSCs. Our findings suggest to harness the capability of NRs to control such a pro-inflammatory axis to design new molecules aimed at selectively hitting CSCs (Figure 7).…”

“…13,14 A kind of 'NF-kB activity addiction' has been therefore proposed to likely render CSCs more susceptible to NF-kB inhibitors than their normal counterparts. [13][14][15] Retinoids are among the most effective pro-differentiating molecules and have been proposed as anticancer agents. 16 Interestingly, it has been shown that all-trans retinoic acid (RA), by inhibiting the activator protein-1, reduces MS formation and the expression of IL6.…”

Double Plant Homeodomain (PHD) Finger Proteins DPF3a and -3b Are Required as Transcriptional Co-activators in SWI/SNF Complex-dependent Activation of NF-κB RelA/p50 Heterodimer

“…It should be pointed out here that in the total protein preparations subcellular localization of natural NF-B is disrupted. These results therefore suggest that the binding potential of RelA to DPF3a and DPF3b is not significantly enhanced by post-translational modifications of RelA triggered by TNF-␣ stimulation (25)(26)(27)(28). Taken together, our findings indicate that both DPF3a and DPF3b have the potential to directly associate with RelA/p50 and the SWI/SNF complex and further that the binding potential is not enhanced by post-translational modifications of NF-B or the SWI/SNF complex triggered by TNF-␣.…”

Butein impairs the protumorigenic activity of malignant pleural mesothelioma cells

“…[13][14][15][16] NFκB and STAT3 appear to play important roles in translating external stimuli (tobacco, dietary agents, alcohol, infectious agents, chemo-and radiotherapy) and microenvironmental stimuli (hypoxia, acidic conditions, immune signals) into pro-tumorigenic signals. [17][18][19][20][21][22] Both NFκB and STAT3 are constitutively activated in many solid tumors, 17,18,23,24 and the two factors functionally crosstalk. 25 In line with this, pharmacological inhibition of NFκB or STAT3 increases the sensitivity of many solid and non-solid tumors to radio-and chemotherapy.…”