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

Rinkenbaugh, Amanda L.; Cogswell, Patricia C.; Calamini, Barbara; Dunn, Denise E.; Persson, Anders I.; Weiss, William A.; Lo, Donald C.; Baldwin, Albert S.

doi:10.18632/oncotarget.12507

Cited by 40 publications

(43 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, elimination of GSCs is considered to be a very effective approach for cure in GBM. A number of studies revealed that the inhibition of various signalling pathways reduced GSC survival and GSC properties . However, given that complete elimination of GSCs alone is difficult using inhibitors of these signal pathways, development of drugs with other strategies targeting GSCs is needed to improve patient survival.…”

Section: Introductionmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A similar effect was observed when the non-canonical NF-κB pathway was impaired through the attenuation of p52 or RelB [48]. A role for non-canonical NF-κB signalling in GSC self-renewal was also suggested by the independent observation that knockdown of RelB blocks the self-renewal activity of patient-derived glioma-initiating cells [49].…”

Section: Role Of Nf-κb In Glioblastoma Stem-like Cellsmentioning

confidence: 68%

NF-κB Signalling in Glioblastoma

Soubannier

Stifani

2017

Biomedicines

View full text Add to dashboard Cite

Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma.

show abstract

“…Glioblastoma (GBM) is the most aggressive form of glioma, resistant to almost all available treatment modalities [1][2][3][4]. The molecular alterations in GBM are wellcharacterized and the involvement of many oncogenic pathways and molecules including NFкB-pathway are known [1,[5][6][7][8][9]. NFкB is an important signaling molecule, upregulating pro-inflammatory and hypoxic responses that contribute to tumor pathology and resistance to therapy [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…The molecular alterations in GBM are wellcharacterized and the involvement of many oncogenic pathways and molecules including NFкB-pathway are known [1,[5][6][7][8][9]. NFкB is an important signaling molecule, upregulating pro-inflammatory and hypoxic responses that contribute to tumor pathology and resistance to therapy [8][9][10]. NFкB activation is known to promote tumor progression through mechanisms such as cell proliferation, apoptosis, angiogenesis, tumor metastasis, proinflammatory response, metabolic reprogramming etc.…”

Section: Introductionmentioning

confidence: 99%

NFкB is a critical transcriptional regulator of atypical cadherin FAT1 in glioma

et al. 2020

View full text Add to dashboard Cite

Background: Overexpression of FAT1 gene and its oncogenic effects have been reported in several cancers. Previously, we have documented upregulation of FAT1 gene in glioblastoma (GBM) tumors which was found to increase the expression of proinflammatory markers, HIF-1α, stemness genes and EMT markers in glioma cells. Here, we reveal NFкB (RelA)/RelA/p65 as the transcriptional regulator of FAT1 gene in GBM cells. Methods: In-silico analysis of FAT1 gene promoter was performed using online bioinformatics tool Promo alggen (Transfac 8.3) to identify putative transcription factor(s) binding motifs. A 4.0 kb FAT1 promoter (− 3220 bp to + 848 bp w.r.t. TSS + 1) was cloned into promoter less pGL3Basic reporter vector. Characterization of FAT1 promoter for transcriptional regulation was performed by in-vitro functional assays using promoter deletion constructs, site directed mutagenesis and ChIP in GBM cells. Results: Expression levels of NFкB (RelA) and FAT1 were found to be increased and positively correlated in GBM tumors (n = 16), REMBRANDT GBM-database (n = 214) and TCGA GBM-database (n = 153). In addition to glioma, positive correlation between NFкB (RelA) and FAT1 expression was also observed in other tumors like pancreatic, hepatocellular, lung and stomach cancers (data extracted from TCGA tumor data). A 4.0 kb FAT1-promoter-construct [− 3220 bp/+ 848 bp, transcription start site (TSS) + 1, having 17 NFкB (RelA) motifs] showed high FAT1 promoter luciferase-activity in GBM cells (U87MG/A172/U373MG). FAT1 promoter deletion-construct pGL3F1 [− 200 bp/+ 848 bp, with 3-NFкB (RelA)-motifs] showed the highest promoter activity. Exposure of GBM cells to known NFкB (RelA)activators [severe-hypoxia/TNF-α/ectopic-NFкB (RelA) + IKBK vectors] led to increased pGL3F1-promoter activity and increased endogenous-FAT1 expression. Conversely, siRNA-mediated NFкB (RelA) knockdown led to decreased pGL3F1-promoter activity and decreased endogenous-FAT1 expression. Deletion of NFкB (RelA)-motif at − 90 bp/− 80 bp [pGL3F1δ1-construct] showed significant decrease in promoter activity. Site directed mutagenesis at-90 bp/− 80 bp and ChIP assay for endogenous-NFкB (RelA) confirmed the importance of this motif in FAT1 expression regulation. Significant reduction in the migration, invasion as well as colony forming capacity of the U87MG glioma cells was observed on siRNA-mediated knockdown of NFкB (RelA). Conclusion: Since FAT1 and NFкB (RelA) are independently known to promote pro-tumorigenic inflammation and upregulate the expression of HIF-1α/EMT/stemness in tumors, targeting the NFкB (RelA)-FAT1 axis may attenuate an important tumor-promoting pathway in GBM. This may also be applicable to other tumors.

show abstract

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

Cited by 40 publications

References 87 publications

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

NF-κB Signalling in Glioblastoma

NFкB is a critical transcriptional regulator of atypical cadherin FAT1 in glioma

Contact Info

Product

Resources

About