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Crosstalk between the STAT3, NF-kB and Notch signaling pathways in glioblastoma stem cells

ABSTRACT: In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48079 | GEO | 2013/06/19

SECONDARY ACCESSION(S): PRJNA208872

REPOSITORIES: GEO

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Project description:Mitochondrial DNA depleted (ρ(0)) human skin fibroblasts (HSF) with suppressed oxidative phosphorylation were characterized by significant changes in the expression of 2100 nuclear genes, encoding numerous protein classes, in NF-κB and STAT3 signaling pathways, and by decreased activity of mitochondrial death pathway, compared to the parental ρ(+) HSF. In contrast, the extrinsic TRAIL/TRAIL-Receptor mediated death pathway remained highly active, and exogenous TRAIL in a combination with cycloheximide (CHX) induced higher levels of apoptosis in ρ(0) cells compared to ρ(+) HSF. Global gene expression analysis using microarray and qRT-PCR demonstrated that mRNA expression levels of many growth factors and their adaptor proteins (FGF13, HGF, IGFBP4, IGFBP6, and IGFL2), cytokines (IL6, ΙL17Β, ΙL18, ΙL19, and ΙL28Β) and cytokine receptors (IL1R1, IL21R, and IL31RA) were substantially decreased after mitochondrial DNA depletion. Some of these genes were targets of NF-κB and STAT3, and their protein products could regulate the STAT3 signaling pathway. Alpha-irradiation further induced expression of several NF-κB/STAT3 target genes, including IL1A, IL1B, IL6, PTGS2/COX2 and MMP12, in ρ(+) HSF, but this response was substantially decreased in ρ(0) HSF. Suppression of the IKK-NF-κB pathway by the small molecular inhibitor BMS-345541 and of the JAK2-STAT3 pathway by AG490 dramatically increased TRAIL-induced apoptosis in the control and irradiated ρ(+) HSF. Inhibitory antibodies against IL6, the main activator of JAK2-STAT3 pathway, added into the cell media, also increased TRAIL-induced apoptosis in HSF, especially after alpha-irradiation. Collectively, our results indicated that NF-κB activation was partially lost in ρ(0) HSF resulting in downregulation of the basal or radiation-induced expression of numerous NF-κB targets, further suppressing IL6-JAK2-STAT3 that in concert with NF-κB regulated protection against TRAIL-induced apoptosis.

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Crosstalk between the STAT3, NF-kB and Notch signaling pathways in glioblastoma stem cells

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