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

被引：56

作者：

Fassl, A.

Tagscherer, K. E.

Richter, J.

Diaz, M. Berriel ^{[1
,2
]}

Llaguno, S. R. Alcantara ^{[3
]}

Campos, B. ^{[4
]}

Kopitz, J. ^{[5
]}

Herold-Mende, C. ^{[4
]}

Herzig, S. ^{[1
,2
]}

Schmidt, M. H. H. ^{[6
]}

Parada, L. F. ^{[3
]}

Wiestler, O. D.

Roth, W. ^{[5
]}

机构：

[1] Univ Heidelberg, Ctr Mol Biol, DKFZ, Joint Div Mol Metab Control, D-6900 Heidelberg, Germany

[2] Univ Heidelberg Hosp, Heidelberg, Germany

[3] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA

[4] Univ Heidelberg, Dept Neurosurg, Heidelberg, Germany

[5] Univ Heidelberg, Inst Pathol, D-6900 Heidelberg, Germany

[6] Goethe Univ Frankfurt, Inst Neurol, Frankfurt, Germany

来源：

ONCOGENE | 2012年 / 31卷 / 44期

关键词：

glioblastoma; apoptosis; Notch1; Mcl-1; EGFR; GROWTH-FACTOR RECEPTOR; NEURAL STEM-CELLS; MALIGNANT GLIOMA; BRAIN-TUMORS; EXPRESSION; PATHWAY; ACTIVATION; ORIGIN; BCL-2; P53;

D O I：

10.1038/onc.2011.615

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4698 / 4708

页数：11

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