Molecular Tumor Pathology, DKFZ, Heidelberg, Germany.
Oncogene. 2012 Nov 1;31(44):4698-708. doi: 10.1038/onc.2011.615. Epub 2012 Jan 16.
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.
Notch1 介导的信号通路在神经干细胞的维持中起核心作用，并有助于成胶质细胞瘤的生长和发展，成胶质细胞瘤是成年人中最常见的恶性脑肿瘤。在这里，我们证明 Notch1 受体通过调节抗凋亡的 Mcl-1 蛋白促进成胶质细胞瘤细胞的存活。Notch1 依赖性的 Mcl-1 调节在转录或翻译后水平上依赖于细胞类型，并通过诱导表皮生长因子受体 (EGFR) 介导。抑制 Notch1 途径可克服凋亡抵抗，并使成胶质细胞瘤细胞对电离辐射、死亡配体 TRAIL（肿瘤坏死因子相关凋亡诱导配体）或 Bcl-2/Bcl-XL 抑制剂 ABT-737 诱导的凋亡敏感。总之，靶向 Notch1 可能代表治疗成胶质细胞瘤的一种有前途的新策略。
