Dose-dependent proteomic analysis of glioblastoma cancer stem cells upon treatment with γ-secretase inhibitor.
Dose-dependent proteomic analysis of glioblastoma cancer stem cells upon treatment with γ-secretase inhibitor.
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DOI：
10.1002/pmic.201000730
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发表时间：
2011-12
期刊：
影响因子：
3.4
通讯作者：
Lubman, David M.
中科院分区：
文献类型：
--
作者：
Dai, Lan;He, Jintang;Liu, Yashu;Byun, Jaeman;Vivekanandan, Anuradha;Pennathur, Subramaniam;Fan, Xing;Lubman, David M.
关键词：
Notch 信号传导已被证明在胶质母细胞瘤 (GBM) 癌症干细胞 (CSC) 中发挥核心作用，我们最近证明，γ-分泌酶抑制剂 (GSI) 阻断 Notch 通路可耗尽 GBM CSC，并在体外和体内阻止肿瘤增殖。为了了解这种转化中涉及的蛋白质组变化，基于全局蛋白质组分析和目标验证阶段，进行了基于剂量依赖性定量质谱（MS）的蛋白质组学研究，其中采用了免疫测定和多反应监测（MRM）测定。由于发现阶段需要进行大量鉴定，因此选择用于确认的推定候选蛋白质构成了挑战。采用多级过滤策略和文献挖掘来沿管道传输最有信心的候选者。我们的结果表明，用 GSI 处理 GBM CSC 会诱导向非致瘤细胞的表型转变，增殖减少、分化增加，以及细胞凋亡增加。我们的数据还表明，葡萄糖代谢受到抑制，NFR2 介导的氧化应激反应减弱，这可能是由于它们与 Notch 信号传导的串扰所致。总体而言，这种基于定量蛋白质组学的剂量依赖性工作补充了我们目前对 GBM CSC 中 GSI 治疗时发生的信号转导事件改变的理解。
Notch Signaling has been demonstrated to have a central role in Glioblastoma (GBM) Cancer Stem Cells (CSCs) and we have demonstrated recently that Notch pathway blockade by γ-secretase inhibitor (GSI) depletes GBM CSCs and prevents tumor propagation both in vitro and in vivo. In order to understand the proteome alterations involved in this transformation, a dose-dependent quantitative mass spectrometry (MS) based proteomic study has been performed based on global proteome profiling and a target verification phase where both Immunoassay and a Multiple Reaction Monitoring (MRM) assay are employed. The selection of putative protein candidates for confirmation poses a challenge due to the large number of identifications from the discovery phase. A multilevel filtering strategy together with literature mining is adopted to transmit the most confident candidates along the pipeline. Our results indicate that treating GBM CSCs with GSI induces a phenotype transformation towards non-tumorigenic cells with decreased proliferation and increased differentiation, as well as elevated apoptosis. Suppressed glucose metabolism and attenuated NFR2-mediated oxidative stress response are also suggested from our data, possibly due to their crosstalk with Notch Signaling. Overall, this quantitative proteomic based dose-dependent work complements our current understanding of the altered signaling events occurring upon the treatment of GSI in GBM CSCs.
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影响因子：
6.4
作者：
Gómez-Pastor R;Pérez-Torrado R;Cabiscol E;Ros J;Matallana E
通讯作者：
Matallana E
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
影响因子：
7
作者：
Bendall, Sean C.;Hughes, Chris;Lajoie, Gilles A.
通讯作者：
Lajoie, Gilles A.
影响因子：
7.2
作者：
Cao, Weidong;Yang, Xiaoliang;Fei, Zhou
通讯作者：
Fei, Zhou
影响因子：
3.7
作者：
Betapudi V
通讯作者：
Betapudi V