靶向抑制 MNK-eIF4E 轴增效TRAIL治疗鼻咽癌的机制研究

项目名称： 靶向抑制 MNK-eIF4E 轴增效TRAIL治疗鼻咽癌的机制研究

项目编号： No.81472773

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 范松青

作者单位： 中南大学

项目金额： 64万元

中文摘要： 磷酸化的MAPK相互作用激酶-1(Mnk1)与其下游的靶基因,真核细胞翻译起始因子-4E（eIF4E) 的磷酸化在肿瘤的侵袭、转移和抗凋亡中具有重要功能。我们前期研究发现MNK-eIF4E轴中关键蛋白的表达异常与鼻咽癌的转移和预后差有关，Mnk1抑制剂CGP57380引起鼻咽癌细胞上调DR5蛋白和下调c-FLIP蛋白的表达，CGP57380增加TRAIL诱导鼻咽癌细胞凋亡。基于前期工作基础，我们提出如下科学假说：MNK-eIF4E轴的激活促进鼻咽癌的进展和转移；靶向抑制MNK-eIF4E轴，可能调控DR5和c-FLIP的表达，通过死亡受体途径诱导凋亡，增加TRAIL治疗鼻咽癌的疗效。本项目将深入研究靶向抑制MNK-eIF4E轴，调控DR5和c-FLIP表达的分子机制，并探讨其诱导凋亡增效TRAIL治疗鼻咽癌的可能性。本项目将为基于MNK-eIF4E轴的鼻咽癌靶向治疗的研究提供新的实验依据。

中文关键词： C03_鼻咽肿瘤；靶向治疗；凋亡；MNK-eIF4E；轴

英文摘要： Phosphorylation of MAP kinase integrating kinase-1(Mnk1) and its downstream target eukaryotic initiation factor 4E (eIF4E) play key roles in the invasion, metastasis and anti-apoptosis of tumor. Our previous results showed that aberrant expression of important proteins in the Mnk-eIF4E axis was associated with lymphnode metastasis and poor prognosis of NPC. The Mnk-1 inhibitor CGP57380 increased expression of DR5 and decreased c-FLIP expression level in the NPC cells. CGP57380 augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) efficiency of inducing NPC cell apoptosis. Basing on our previous research results, we put forward the scientific idea: Activation of Mnk-eIF4E axis play critical roles in the progress and metastasis of NPC. Targeting inhibition of the Mnk-eIF4E axis may augment the effects on TRAIL-induced apoptosis which is triggered by activation of death receptor signaling pathways through regulating the expression of DR5 and c-FLIP protein in NPC cells. In this research project, we will further investigate the molecular mechanism of expression of DR5 and c-FLIP protein which is regulated by targeting inhibition of the Mnk-eIF4E axis. Also, we will study the TRAIL efficiency of inducing apoptosis to improve the treatment of NPC with targeting inhibition of the Mnk-eIF4E axis. The project might provide the valuable new experimental evidence for targeting treatment of NPC.

英文关键词： Nasopharyngeal tumor;Targeted therapy;Apoptosis;MNK-eIF4E axis