Targeting NF-κB in glioblastoma: A therapeutic approach

Friedmann‐Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M.

doi:10.1126/sciadv.1501292

Cited by 119 publications

(96 citation statements)

References 36 publications

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“…S8D,E). In conjunction with this result, a survivin promoter reporter construct (−1000 base pairs [bp] to +1) containing these NF-κB response elements showed that promoter activity was stimulated upon vIII-CM treatment and that its activity was efficiently inhibited by IκB superrepressor (IκB-SR) (Friedmann-Morvinski et al 2016) or deletions of the three NF-κB-binding sites (Fig. 4C).…”

Section: Nf-κb Regulates Survivin Expression In Gbmmentioning

confidence: 64%

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Zanca

Villa

Benítez³

et al. 2017

Genes Dev.

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In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.

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Section: Nf-κb Regulates Survivin Expression In Gbmmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

Zanca

Villa

Benítez³

et al. 2017

Genes Dev.

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“…Moreover, MWCNTs induced the expression of a panel of cell cycle control genes in WT lungs, but induction was significantly reduced in Timp1 KO lungs (Figure 5A and B); MWCNTs stimulated the proliferation of fibroblasts in WT lungs but not in Timp1 KO lungs (Figure 5C); and co-treatment of primary mouse lung fibroblasts with MWCNTs and TIMP1 neutralizing antibodies largely reduced the proliferation of fibroblasts induced by MWCNTs in vitro (Figure S12). Other studies have also suggested a role for TIMP1 in boosting cell proliferation in several in vitro and in vivo models (Bertaux et al, 1991; Chesler et al, 1995; Friedmann-Morvinski et al, 2016; Hayakawa et al, 1992; Xia et al, 2012). Therefore, our results describe a novel underlying mechanism for MWCNT-induced lung fibrosis through the TIMP1-dependent proliferation of fibroblasts.…”

Section: Discussionmentioning

confidence: 95%

“…For instance, MMPs have both inhibitory and stimulatory activities toward fibrosis in addition to ECM degradation (Giannandrea & Parks, 2014). On the other hand, the MMP-independent functions of TIMP1, such as promoting cell proliferation and survival, have received increasing attention, particularly for cancer cells (Friedmann-Morvinski et al, 2016; Xia et al, 2012). In this regard, our study provides the in vivo evidence to support the MMP-independent function of TIMP1 in promoting cell proliferation in induced organ fibrosis.…”

Section: Discussionmentioning

confidence: 99%

TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation

Dong

2016

Nanotoxicology

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Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) may cause fibrosing lesions in animal lungs, raising health concerns about such exposure in humans. The mechanisms underlying fibrosis development remain unclear, but they are believed to involve the dysfunction of fibroblasts and myofibroblasts. Using a mouse model of MWCNT exposure, we found that the tissue inhibitor of metalloproteinase 1 (Timp1) gene was rapidly and highly induced in the lungs by MWCNTs in a time- and dose-dependent manner. Concomitantly, a pronounced elevation of secreted TIMP1 was observed in the bronchoalveolar lavage (BAL) fluid and serum. Knockout (KO) of Timp1 in mice caused a significant reduction in fibrotic focus formation, collagen fiber deposition, recruitment of fibroblasts and differentiation of fibroblasts into myofibroblasts in the lungs, indicating that TIMP1 plays a critical role in the pulmonary fibrotic response to MWCNTs. At the molecular level, MWCNT exposure significantly increased the expression of the cell proliferation markers Ki-67 and PCNA and a panel of cell cycle-controlling genes in the lungs in a TIMP1-dependent manner. MWCNT-stimulated cell proliferation was most prominent in fibroblasts but not myofibroblasts. Furthermore, MWCNTs elicited a significant induction of CD63 and integrin β1 in lung fibroblasts, leading to the formation of a TIMP1/CD63/integrin β1 complex on the surface of fibroblasts in vivo and in vitro, which triggered the phosphorylation and activation of Erk1/2. Our study uncovers a new pathway through which induced TIMP1 critically modulates the pulmonary fibrotic response to MWCNTs by promoting fibroblast activation and proliferation via the TIMP1/CD63/integrin β1 axis and ERK signaling.

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“…Others have identified alterations in the NF-κB pathway itself, with a subset of GBMs harboring monoallelic NFKBIA (gene name for IκBα) deletions and others expressing high levels of miR-30e* which targets IκBα [34, 35]. Consistent with the involvement of NF-κB signaling in GBM, recent work demonstrated that treatment with a NEMO-binding domain (NBD) peptide that blocks interactions between NEMO and IKKα/β slowed tumor growth in both a human glioma xenograft and a genetic mouse model of glioma [36]. …”

Section: Introductionmentioning

confidence: 99%

IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance

et al. 2016

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Glioblastoma multiforme (GBM) carries a poor prognosis and continues to lack effective treatments. Glioblastoma stem cells (GSCs) drive tumor formation, invasion, and drug resistance and, as such, are the focus of studies to identify new therapies for disease control. Here, we identify the involvement of IKK and NF-κB signaling in the maintenance of GSCs. Inhibition of this pathway impairs self-renewal as analyzed in tumorsphere formation and GBM expansion as analyzed in brain slice culture. Interestingly, both the canonical and non-canonical branches of the NF-κB pathway are shown to contribute to this phenotype. One source of NF-κB activation in GBM involves the TGF-β/TAK1 signaling axis. Together, our results demonstrate a role for the NF-κB pathway in GSCs and provide a mechanistic basis for its potential as a therapeutic target in glioblastoma.

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Targeting NF-κB in glioblastoma: A therapeutic approach

Abstract: Inhibition of the transcription factor NF-κB or its target genes should be considered for the treatment of patients with glioblastoma multiforme.

Cited by 119 publications

References 36 publications

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

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

TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation

IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance

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