MAPK signal-integrating kinase controls cap-independent translation and cell type-specific cytotoxicity of an oncolytic poliovirus.
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).
Goetz
Christian
C
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Everson
Richard G
RG
Zhang
Linda C
LC
Gromeier
Matthias
M
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050130:Oncolytic Virotherapy; D010766:Phosphorylation; D017955:Poliovirus / Q000502:physiology*; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D012315:RNA Caps / Q000235:genetics*; D015398:Signal Transduction; D053586:Virus Internalization; D014779:Virus Replication
D039561:Eukaryotic Initiation Factor-4E; D047428:Protein Kinase Inhibitors; D012315:RNA Caps; C106281:Mknk1 protein, mouse; D019870:1-Phosphatidylinositol 4-Kinase; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases