Nuclear factor-κB in glioblastoma: insights into regulators and targeted therapy

Abstract

Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-κB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-κB system, discuss the role of NF-κB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-κB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-κB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-κB-dependent pathways can make a significant contribution to the management of GBM.

Culture on 3D Chitosan‐Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells

“…Similar coordinated gene expression was also observed for the Hippo pathway, which functions during early development to establish cellular polarity . Other pathway members showing modest increased expression include Notch2, STAT3 which promotes acquisition of mesenchymal phenotype, IKB1B, a modulator of the NFKB stress response pathway, and SAV1, a modulator of the Hippo pathway . These findings are strong evidence that CHA scaffolds provide an environment that promotes the growth of CSCs that are the progenitors of GBM.…”

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

“…S11A-D). We also tested NF-κB pathway inhibitor MLN120B (IKKβ) (Cahill et al 2016) in combination with gefitinib, and similar results were obtained (Supplemental Fig. S11A-D).…”

“…When IκB is targeted for proteasomal degradation by phosphorylation, active NF-κB migrates to the nucleus and activates the transcription of genes involved in cancer progression and chemoresistance; for example, Bcl-2, Bclxl, Cox2, IAP, and CCND1. A variety of stimuli can activate NF-κB-mediated transcription, among which wtEGFR and EGFRvIII have been reported to activate NF-κB (Dan et al 2008;Tanaka et al 2011;Cahill et al 2016). In this regard, NF-κB has been shown to be a major molecular driver of chemotherapy and radiotherapy resistance in GBM (Tanaka et al 2011;Bhat et al 2013;Cahill et al 2016;Friedmann-Morvinski et al 2016).…”

“…A variety of stimuli can activate NF-κB-mediated transcription, among which wtEGFR and EGFRvIII have been reported to activate NF-κB (Dan et al 2008;Tanaka et al 2011;Cahill et al 2016). In this regard, NF-κB has been shown to be a major molecular driver of chemotherapy and radiotherapy resistance in GBM (Tanaka et al 2011;Bhat et al 2013;Cahill et al 2016;Friedmann-Morvinski et al 2016). To inhibit survivin expression, we chose the epigenetic regulator JQ1, which targets the bromodomain-containing factor BRD4, known to maintain NF-κB in an active state and regulate the enhancer-mediated function of this transcription factor (Brown et al 2014;Zou et al 2014).…”

Amentoflavone Induces Apoptosis and Inhibits NF-ĸBmodulated Anti-apoptotic Signaling in Glioblastoma Cells

“…DNA fragmentation initiated by active caspase-3 can be triggered via intrinsic and extrinsic apoptotic signaling pathways. High expression of cleaved caspase-8 and active caspase-3 are positive prognostic indicators for patients with glioma (1,18). Figure 2B and D indicate amentoflavone significantly induced expression of active caspase-3 and -8, while Figure 2C shows amentoflavone significantly induced loss of Ψm, all associated with apoptosis.…”