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.
authors.affiliation: Molecular Tumor Pathology, DKFZ, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fassl
authors.forename: K E
authors.initials: KE
authors.lastname: Tagscherer
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.forename: M
authors.initials: M
authors.lastname: Berriel Diaz
authors.forename: S R
authors.initials: SR
authors.lastname: Alcantara Llaguno
authors.forename: B
authors.initials: B
authors.lastname: Campos
authors.forename: J
authors.initials: J
authors.lastname: Kopitz
authors.forename: C
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: S
authors.initials: S
authors.lastname: Herzig
authors.forename: M H H
authors.initials: MHH
authors.lastname: Schmidt
authors.forename: L F
authors.initials: LF
authors.lastname: Parada
authors.forename: O D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: W
authors.initials: W
authors.lastname: Roth
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf