MAPK signal-integrating kinase controls cap-independent translation and cell type-specific cytotoxicity of an oncolytic poliovirus.

Molecular Therapy : the Journal of the American Society of Gene Therapy
Christian GoetzMatthias Gromeier

Abstract

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).

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Citations

Apr 1, 2011·Journal of Virology·Eric S WangMatthias Gromeier
Oct 11, 2011·Future Virology·Christian GoetzMatthias Gromeier
Jun 19, 2014·Cancer·Michael C BrownMatthias Gromeier
Jun 18, 2015·Current Opinion in Virology·Michael C Brown, Matthias Gromeier
Jul 16, 2015·Human Gene Therapy·Dmitriy Zamarin, Sari Pesonen
May 23, 2015·Human Vaccines & Immunotherapeutics·Pascal R A BuijsBernadette G van den Hoogen
Jan 22, 2011·Virology·Ross E RhoadesRalph Feuer
Oct 28, 2014·Oncogene·Y KomatsuK Hirasawa
Jul 28, 2016·Biochemistry. Biokhimii︠a︡·A N Lukashev, A A Zamyatnin
Dec 23, 2016·Cellular and Molecular Life Sciences : CMLS·Jutta SteinbergerJerry Pelletier
Feb 8, 2018·Annual Review of Medicine·Matthias Gromeier, Smita K Nair
Dec 21, 2018·Frontiers in Oncology·John LynesEdjah Nduom

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