Cap-dependent translational control of oncolytic measles virus infection in malignant mesothelioma
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Blake A. Jacobson1, Ahad A. Sadiq1, Shaogeng Tang1, Joe Jay-Dixon1, Manish R. Patel1, Jeremy Drees2, Brent S. Sorenson3, Stephen J. Russell4,5 and Robert A. Kratzke1,2
1Department of Medicine, University of Minnesota, Minneapolis, MN, USA
2Department of Surgery, University of Minnesota, Minneapolis, MN, USA
3Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
4Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
5Division of Hematology, Mayo Clinic, Rochester, MN, USA
Robert A. Kratzke, email: [email protected]
Keywords: measles virus, oncolytic virus, translation, cap-dependent, mesothelioma
Received: March 12, 2017 Accepted: May 22, 2017 Published: June 27, 2017
Malignant mesothelioma has a poor prognosis for which there remains an urgent need for successful treatment approaches. Infection with the Edmonston vaccine strain (MV-Edm) derivative of measles virus results in lysis of cancer cells and has been tested in clinical trials for numerous tumor types including mesothelioma. Many factors play a role in MV-Edm tumor cell selectivity and cytopathic activity while also sparing non-cancerous cells. The MV-Edm receptor CD46 (cluster of differentiation 46) was demonstrated to be significantly higher in mesothelioma cells than in control cells. In contrast, mesothelioma cells are not reliant upon the alternative MV-Edm receptor nectin-4 for entry. MV-Edm treatment of mesothelioma reduced cell viability and also invoked apoptotic cell death. Forced expression of eIF4E or translation stimulation following IGF-I (insulin-like growth factor 1) exposure strengthened the potency of measles virus oncolytic activity. It was also shown that repression of cap-dependent translation by treatment with agents [4EASO, 4EGI-1] that suppress host cell translation or by forcing cells to produce an activated repressor protein diminishes the strength of oncolytic viral efficacy.
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