Inhibition of Notch1 signaling overcomes resistance to the death ligand Trail by specificity protein 1-dependent upregulation of death receptor 5

The Notch1 signaling pathway contributes to tumorigenesis by influencing differentiation, proliferation and apoptosis. Here, we demonstrate that inhibition of the Notch1 signaling pathway sensitizes glioblastoma cell lines and glioblastoma initiating cells to apoptosis induced by the death ligand TR...

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Bibliographic Details
Published in:Cell death & disease 2015-10, Vol.6 (10), p.e1921-e1921
Main Authors: Fassl, A, Tagscherer, K E, Richter, J, De-Castro Arce, J, Savini, C, Rösl, F, Roth, W
Format: Article
Language:English
Subjects:
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Antibodies
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Biochemistry
Biomedical and Life Sciences
Caspase 8 - metabolism
Cell Biology
Cell Culture
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression - drug effects
Gene Knockdown Techniques
Humans
Immunology
Life Sciences
Original
original-article
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
Signal Transduction
Sp1 Transcription Factor - metabolism
TNF-Related Apoptosis-Inducing Ligand - pharmacology
Up-Regulation
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Description
Summary:The Notch1 signaling pathway contributes to tumorigenesis by influencing differentiation, proliferation and apoptosis. Here, we demonstrate that inhibition of the Notch1 signaling pathway sensitizes glioblastoma cell lines and glioblastoma initiating cells to apoptosis induced by the death ligand TRAIL. This sensitization occurs through transcriptional upregulation of the death receptor 5 (DR5, TRAIL-R2). The increase in DR5 expression is abrogated by concomitant repression of the transcription factor Sp1, which directly binds to the DR5 promoter in the absence of Notch1 as revealed by chromatin immunoprecipitation. Consistent with these findings, Notch1 inhibition resulted in increased DR5 promoter activity, which was impaired by mutation of one out of two Sp1-binding sites within the proximal DR5 promoter. Moreover, we demonstrate that JNK signaling contributes to the regulation of DR5 expression by Notch1. Taken together, our results identify Notch1 as key driver for TRAIL resistance and suggest Notch1 as a promising target for anti-glioblastoma therapy.
ISSN:2041-4889
2041-4889
DOI:10.1038/cddis.2015.261