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The State of The Jak/Stat Pathway Affects the Sensitivity of Tumor Cells to Oncolytic Enteroviruses

  • MOLECULAR CELL BIOLOGY
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Abstract

A test of the sensitivity of seven colon cancer cell lines to a panel of 12 nonpathogenic human enteroviruses revealed significant differences in the ability of tumor cells to become infected and replicate different viral strains. Among the factors that can affect the sensitivity of cells to viruses are differences in the state of the mechanisms of antiviral protection, associated with a reaction to type I interferons. Using the two colon cancer cell lines CaCo2 and LIM1215 as a model, significant differences were revealed in the ability of cells to defend themselves against virus infection after 16 hours of treatment with 1000 units/mL of interferon-alpha. To study the effect of the state of the interferon response system, represented by the Jak/STAT signaling pathway, on the sensitivity of cells to different strains of enteroviruses, HEK293T cell lines were used. These are capable of supporting replication of each of the tested enteroviruses, as well as maintaining the ability to protect against viral infection after the treatment with interferon. Using the CRISPR/Cas9 system, HEK293T sublines with knockouts of the IFNAR1 and STAT2 genes were obtained. The sensitivity of control and knockout cells to infection with five strains of enteroviruses and the vesicular stomatitis virus was analyzed. It was noted that knockout of the IFNAR1 and STAT2 genes resulted in an increased sensitivity to all tested viruses. In knockout cells, the levels of reproduction of the vaccine dervied of poliovirus type 1, Echoviruses 7 and 30, and Coxsackie viruses B5 and A7 were also significantly increased in comparison with the control HEK293T cells. Thus, deficiencies in the Jak/STAT signaling pathway in tumor cells lead to an overall increase in the sensitivity to oncolytic viruses.

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Funding

The study was supported by the Russian Foundation for Basic Research (project no. 18-29-01059) and the Center for Strategic Planning and Assessment of Biomedical Health Risks of the Federal Midical-Biological Agency of the Russian Federation (grant no. 1.1597).

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119991, Moscow, Russia

    T. H. Le, A. V. Lipatova, M. A. Volskaya, O. A. Tikhonova & P. M. Chumakov

  2. Moscow Institute of Physics and Technology, 141701, Dolgoprudny, Russia

    T. H. Le

  3. Chumakov Federal Scientific Center for Research and Development of Immunobiological Products, Russian Academy of Sciences, 108819, Moscow, Russia

    P. M. Chumakov

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  1. T. H. Le
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  2. A. V. Lipatova
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  3. M. A. Volskaya
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  4. O. A. Tikhonova
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  5. P. M. Chumakov
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Correspondence to P. M. Chumakov.

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The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Le, T.H., Lipatova, A.V., Volskaya, M.A. et al. The State of The Jak/Stat Pathway Affects the Sensitivity of Tumor Cells to Oncolytic Enteroviruses. Mol Biol 54, 570–577 (2020). https://doi.org/10.1134/S002689332004010X

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  • DOI: https://doi.org/10.1134/S002689332004010X

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