MAPK Signal-integrating Kinase Controls Cap-independent Translation and Cell Type-specific Cytotoxicity of an Oncolytic Poliovirus
MAPK Signal-integrating Kinase Controls Cap-independent Translation and Cell Type-specific Cytotoxicity of an Oncolytic Poliovirus
复制标题
DOI：
10.1038/mt.2010.145
复制
发表时间：
2010-11-01
影响因子：
12.4
通讯作者：
Gromeier, Matthias
中科院分区：
文献类型：
--
作者：
Goetz, Christian;Everson, Richard G.;Gromeier, Matthias
许多动物病毒在转化细胞中表现出良好的生长能力，这一特性已被用于开发新的抗癌疗法。尽管有压倒性的证据证明这种现象，但对大多数病毒来说，对肿瘤细胞杀伤的分子机制的理解是基本的。我们在这里报告的原型溶瘤脊髓灰质炎病毒（PV），PVSRIPO，在胶质母细胞瘤（GBM）的生长和细胞毒性的促进丝裂原活化蛋白激酶（MAPK）的信号整合激酶1（Mnk 1）和其主要底物，真核起始因子（eIF）4 E会聚。通过致癌Ras的表达诱导Mnk 1催化的eIF 4 E磷酸化显著增强了抗性细胞中PVSRIPO的翻译、复制和细胞毒性。这种效应被Mnk 1组成型活性形式的表达所模拟，并与亚基因组报告RNA的翻译增强相关。我们的研究结果暗示Mnk 1活性刺激PVSRIPO帽独立翻译，这种作用可以通过抑制磷酸肌醇-3激酶（PI 3 K）协同增强。
Many animal viruses exhibit proficient growth in transformed cells, a property that has been harnessed for the development of novel therapies against cancer. Despite overwhelming evidence for this phenomenon, understanding of the molecular mechanisms enabling tumor-cell killing is rudimentary for most viruses. We report here that growth and cytotoxicity of the prototype oncolytic poliovirus (PV), PVSRIPO, in glioblastoma multiforme (GBM) is promoted by mitogen-activated protein kinases (MAPKs) converging on the MAPK signal-integrating kinase 1 (Mnk1) and its primary substrate, the eukaryotic initiation factor (eIF) 4E. Inducing Mnk1-catalyzed eIF4E phosphorylation through expression of oncogenic Ras substantially enhanced PVSRIPO translation, replication, and cytotoxicity in resistant cells. This effect was mimicked by expression of constitutively active forms of Mnk1 and correlated with enhanced translation of subgenomic reporter RNAs. Our findings implicate Mnk1 activity in stimulation of PVSRIPO cap-independent translation, an effect that can be synergistically enhanced by inhibition of the phosphoinositide-3 kinase (PI3K).