MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas
MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas
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DOI：
10.1172/jci70198
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Hemmings, Brian A.
中科院分区：
文献类型：
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作者：
Grzmil, Michal;Huber, Roland M.;Hemmings, Brian A.
恶性胶质瘤中高水平的哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）活性促进肿瘤进展，表明靶向mTORC 1具有作为治疗策略的潜力。值得注意的是，神经胶质瘤患者的临床试验显示，雷帕霉素类似物（rapalogs）的疗效有限，表明耐药机制的激活。靶向去除MAPK相互作用的Ser/Thr激酶1（MNK 1）通过一种不明确的机制使胶质瘤细胞对mTORC 1抑制剂雷帕霉素敏感。在这里，我们分析了MNK 1和mTORC 1信号通路如何调节翻译起始复合物的组装，使用帽类似物m（7）GTP富集胶质瘤细胞中的起始复合物，然后进行基于质谱的定量蛋白质组学。真核生物翻译起始因子4 E（eIF 4 E）与eIF 4 E结合蛋白1（4 EBP 1）的结合受mTORC 1通路的调节，而通过CGP 57380或MNK 1敲低对MNK活性的药理学阻断，沿着通过RAD 001对mTORC 1的抑制，增加了4 EBP 1与eIF 4 E的结合。此外，MNK 1和mTORC 1联合抑制可显著抑制4 EBP 1丝氨酸65位磷酸化、神经胶质瘤细胞中的蛋白质合成和增殖，并减少原位胶质母细胞瘤（GBM）小鼠模型中的肿瘤生长。GBM样品的免疫组织化学分析显示4 EBP 1磷酸化增加。综上所述，我们的数据表明，雷帕霉素类似物激活的MNK 1信号通过调节4 EBP 1促进胶质瘤生长，并表明mTORC 1和MNK 1通路之间的分子串扰具有治疗上的潜力。
High levels of mammalian target of rapamycin complex 1 (mTORC1) activity in malignant gliomas promote tumor progression, suggesting that targeting mTORC1 has potential as a therapeutic strategy. Remarkably, clinical trials in patients with glioma revealed that rapamycin analogs (rapalogs) have limited efficacy, indicating activation of resistance mechanisms. Targeted depletion of MAPK-interacting Ser/Thr kinase 1 (MNK1) sensitizes glioma cells to the mTORC1 inhibitor rapamycin through an indistinct mechanism. Here, we analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, using the cap analog m(7)GTP to enrich for initiation complexes in glioma cells followed by mass spectrometry-based quantitative proteomics. Association of eukaryotic translation initiation factor 4E (eIF4E) with eIF4E-binding protein 1 (4EBP1) was regulated by the mTORC1 pathway, whereas pharmacological blocking of MNK activity by CGP57380 or MNK1 knockdown, along with mTORC1 inhibition by RAD001, increased 4EBP1 binding to eIF4E. Furthermore, combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model. Immunohistochemical analysis of GBM samples revealed increased 4EBP1 phosphorylation. Taken together, our data indicate that rapalog-activated MNK1 signaling promotes glioma growth through regulation of 4EBP1 and indicate a molecular cross-talk between the mTORC1 and MNK1 pathways that has potential to be exploited therapeutically.