Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

A. Fassl; K. E. Tagscherer; J. Richter; M. Berriel Diaz; S. R. Alcantara Llaguno; B. Campos; J. Kopitz; C. Herold-Mende; S. Herzig; M. H H Schmidt; L. F. Parada; O. D. Wiestler; W. Roth

doi:10.1038/onc.2011.615

Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

A. Fassl, K. E. Tagscherer, J. Richter, M. Berriel Diaz, S. R. Alcantara Llaguno, B. Campos, J. Kopitz, C. Herold-Mende, S. Herzig, M. H H Schmidt, L. F. Parada, O. D. Wiestler, W. Roth

Developmental Biology

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.

Original language	English (US)
Pages (from-to)	4698-4708
Number of pages	11
Journal	Oncogene
Volume	31
Issue number	44
DOIs	https://doi.org/10.1038/onc.2011.615
State	Published - Nov 1 2012

Keywords

EGFR
Mcl-1
Notch1
apoptosis
glioblastoma

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2011.615

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Fassl, A., Tagscherer, K. E., Richter, J., Berriel Diaz, M., Alcantara Llaguno, S. R., Campos, B., Kopitz, J., Herold-Mende, C., Herzig, S., Schmidt, M. H. H., Parada, L. F., Wiestler, O. D., & Roth, W. (2012). Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1. Oncogene, 31(44), 4698-4708. https://doi.org/10.1038/onc.2011.615

Fassl, A, Tagscherer, KE, Richter, J, Berriel Diaz, M, Alcantara Llaguno, SR, Campos, B, Kopitz, J, Herold-Mende, C, Herzig, S, Schmidt, MHH, Parada, LF, Wiestler, OD & Roth, W 2012, 'Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1', Oncogene, vol. 31, no. 44, pp. 4698-4708. https://doi.org/10.1038/onc.2011.615

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title = "Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1",

abstract = "The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.",

keywords = "EGFR, Mcl-1, Notch1, apoptosis, glioblastoma",

author = "A. Fassl and Tagscherer, {K. E.} and J. Richter and {Berriel Diaz}, M. and {Alcantara Llaguno}, {S. R.} and B. Campos and J. Kopitz and C. Herold-Mende and S. Herzig and Schmidt, {M. H H} and Parada, {L. F.} and Wiestler, {O. D.} and W. Roth",

note = "Funding Information: We thank Tabea Sinkovic and Martina Keith for technical assistance. We further thank Anja Reimann (Molecular Metabolic Control, DKFZ, Heidelberg, Germany) for help with purification of recombinant adenoviruses, David Capper, David Reuss and Andreas v Deimling (Department of Neuropathology, University of Heidelberg, Germany) for providing histological sections of glioblastomas and Tamara Quandel, Lodovica Borghese, Philipp Koch and Oliver Br{\"u}stle (Institute of Reconstructive Neurobiology, Life and Brain, Bonn, Germany) for providing cell pellets and RNA from neural stem cells. This work was supported by a grant from the Deutsche Krebshilfe to WR (German Cancer Aid, Max Eder Program).",

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AU - Richter, J.

AU - Berriel Diaz, M.

AU - Alcantara Llaguno, S. R.

AU - Campos, B.

AU - Kopitz, J.

AU - Herold-Mende, C.

AU - Herzig, S.

AU - Schmidt, M. H H

AU - Parada, L. F.

AU - Wiestler, O. D.

AU - Roth, W.

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Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

Abstract

Keywords

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