Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.
Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.
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DOI：
10.1177/1947601910383564
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Griffin JD
中科院分区：
文献类型：
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作者：
Chen J;Kesari S;Rooney C;Strack PR;Chen J;Shen H;Wu L;Griffin JD
胶质母细胞瘤是最常见的恶性脑肿瘤，具有高增殖率和侵袭性的特点。由于Notch信号的异常与许多人类癌症的发生有关，我们在这里研究了Notch信号在GBM中的作用。我们发现在GBM细胞系和人GBM来源的神经球中存在Notch信号的异常激活。通过表达显性负性Notch共激活剂MAML1或γ分泌酶抑制剂MRK003抑制Notch信号转导，可显著抑制GBM细胞的体外和体内生长。敲除单个Notch受体表明Notch1和Notch2受体对GBM细胞的生长有不同的贡献，其中Notch2起主导作用。此外，阻断Notch信号可抑制体外和体内人GBM来源神经球的增殖。我们的总体数据表明，Notch信号对GBM的最佳生长有重要作用，这有力地支持了Notch途径是GBM的一个有前途的治疗靶点。
Glioblastoma (GBM) is the most common malignant brain tumor that is characterized by high proliferative rate and invasiveness. Since dysregualtion of Notch signaling is implicated in the pathogenesis of many human cancers, here we investigated the role of Notch signaling in GBM. We found that there is aberrant activation of Notch signaling in GBM cell lines and human GBM-derived neurospheres. Inhibition of Notch signaling via the expression of a dominant negative form of the Notch co-activator, mastermind-like 1 (DN-MAML1) or the treatment of a γ-secretase inhibitor (GSI) MRK-003 resulted in a significant reduction in GBM cell growth in vitro and in vivo. Knockdown of individual Notch receptors revealed that Notch1 and Notch2 receptors differentially contributed to GBM cell growth, with Notch2 having a predominant role. Furthermore, blockade of Notch signaling inhibited the proliferation of human GBM-derived neurospheres in vitro and in vivo. Our overall data indicate that Notch signaling contributes significantly to optimal GBM growth, strongly supporting that the Notch pathway is a promising therapeutic target for GBM.