Notch promotes radioresistance of glioma stem cells.
Notch promotes radioresistance of glioma stem cells.
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DOI：
10.1002/stem.261
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发表时间：
2010-01
期刊：
影响因子：
5.2
通讯作者：
Sullenger, Bruce A.
中科院分区：
文献类型：
--
作者：
Wang, Jialiang;Wakeman, Timothy P.;Lathia, Justin D.;Hjelmeland, Anita B.;Wang, Xiao-Fan;White, Rebekah R.;Rich, Jeremy N.;Sullenger, Bruce A.
放射治疗是神经胶质瘤最有效的非手术治疗方法。然而，神经胶质瘤具有高度的放射抗性，并且复发几乎是普遍的。我们实验室和其他小组的结果表明，癌症干细胞有助于神经胶质瘤和乳腺癌的放射抗性。 Notch 通路与干细胞命运决定和癌症密切相关。在这项研究中，我们发现用γ-分泌酶抑制剂（GSI）抑制Notch通路使神经胶质瘤干细胞对临床相关剂量的辐射更加敏感。 GSI 会增强辐射诱导的细胞死亡并损害神经胶质瘤干细胞的克隆存活，但不会损害非干神经胶质瘤细胞。同样，Notch1 或 Notch2 的敲除增加了神经胶质瘤干细胞的放射敏感性。 GSI 放射增敏作用的特异性通过保护神经胶质瘤干细胞免受辐射的 Notch1 或 Notch2 组成型活性细胞内结构域的表达得到证实。 GSI 的 Notch 抑制不会改变放射后神经胶质瘤干细胞的 DNA 损伤反应，但会损害放射诱导的 Akt 激活并上调 Mcl-1 (Mcl-1s) 的截短凋亡亚型的水平。综上所述，我们的结果表明 Notch 在促进神经胶质瘤干细胞的放射抗性方面发挥着关键作用。抑制Notch信号有望提高当前神经胶质瘤放疗的效率。
Radiotherapy represents the most effective nonsurgical treatments for gliomas. Yet, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we showed that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) rendered the glioma stem cells more sensitive to radiation at clinically relevant doses. GSIs enhanced radiation-induced cell death and impaired clonogenic survival of glioma stem cells, but not non-stem glioma cells. Similarly, knockdown of Notch1 or Notch2 increased radiosensitivity of glioma stem cells. The specificity of the radiosensitizing effects of GSIs was confirmed by expression of the constitutively active intracellular domains of Notch1 or Notch2 that protected glioma stem cells against radiation. Notch inhibition with GSIs did not alter the DNA damage response of glioma stem cells following radiation, but rather impaired radiation-induced Akt activation and upregulated levels of the truncated apoptotic isoform of Mcl-1 (Mcl-1s). Taken together, our results suggest a critical role of Notch to promote radioresistance of glioma stem cells. Inhibition of Notch signaling holds promise to improve the efficiency of current radiotherapy in glioma treatment.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
8
作者：
Curry, CL;Reed, LL;Foreman, KE
通讯作者：
Foreman, KE
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
影响因子：
8.8
作者：
Coelho, D;Holl, V;Bischoff, P
通讯作者：
Bischoff, P
影响因子：
11.2
作者：
Ban J;Bennani-Baiti IM;Kauer M;Schaefer KL;Poremba C;Jug G;Schwentner R;Smrzka O;Muehlbacher K;Aryee DN;Kovar H
通讯作者：
Kovar H