1. Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1.
- Author
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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, and Roth W
- Subjects
- Apoptosis genetics, Cell Line, Tumor, Cell Proliferation, Cell Survival genetics, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-raf metabolism, RNA Processing, Post-Transcriptional, Receptor, Notch1 genetics, Transcription, Genetic, ErbB Receptors metabolism, Glioblastoma genetics, Glioblastoma metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Receptor, Notch1 metabolism, Signal Transduction
- 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.
- Published
- 2012
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