Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

// Irina A Tarasova 1, * , Alesya V Tereshkova 2, 3, * , Anna A Lobas 1, 4 , Elizaveta M Solovyeva 1, 4 , Alena S Sidorenko 2 , Vladimir Gorshkov 5 , Frank Kjeldsen 5 , Julia A Bubis 1, 4 , Mark V Ivanov 1, 4 , Irina Y Ilina 6 , Sergei A Moshkovskii 6, 7 , Peter M Chumakov 2, 3 and Mikhail V Gorshkov 1, 4 1 Talrose Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia 2 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 3 Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Sciences, 142782 Moscow, Russia 4 Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia 5 Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark 6 Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia 7 Pirogov Russian National Research Medical University, 117997 Moscow, Russia * These authors contributed equally to this work Correspondence to: Irina A Tarasova, email: iatarasova@yandex.ru Peter M Chumakov, email: chumakovpm@yahoo.com Keywords: comparative proteomics; glioblastoma multiforme; oncolytic virotherapy; interferon signaling alterations; JAK/STAT pathway Received: June 07, 2017      Accepted: October 27, 2017      Published: November 29, 2017 ABSTRACT An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in two glioblastoma multiforme (GBM) cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. However, we observed a deficiency in STAT2 protein in the VSV-sensitive cell line that suggests a de-regulation of the JAK/STAT/IRF9 signaling. The study has shown that the up-regulation of IRG proteins induced by the IFNα treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses. The approach can be useful for discovering the biomarkers that predict a potential sensitivity of individual glioblastoma tumors to oncolytic virus therapy.