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Kaposi's sarcoma herpesvirus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas

Oncogene volume 32, pages 1091–1098 (2013)Cite this article

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Abstract

Primary effusion lymphomas (PELs) are aggressive Kaposi's sarcoma herpesvirus (KSHV)-induced malignancies with median survival time <6 months post-diagnosis. Mutations in the TP53 gene seldom occur in PELs, suggesting that genetic alterations in the TP53 are not selected during PEL progression. We have reported that p53 reactivation by an inhibitor of the p53–MDM2 interaction, Nutlin-3, induces selective and massive apoptosis in PEL cells leading to efficient anti-tumor activity in a subcutaneous xenograft model for PEL. Here, we show compelling anti-tumor activity of Nutlin-3 in the majority of intraperitoneal PEL xenografts in vivo. Interestingly, our results demonstrate that spontaneous induction of viral lytic replication in tumors could drastically attenuate the p53-dependent apoptotic response to Nutlin-3. Moreover, viral reactivation compromised p53-dependent apoptosis in PEL cells treated with genotoxic anti-cancer agents doxorubicin and etoposide. We have recently demonstrated that the Ser/Thr kinases Pim 1 and 3 are required to trigger induction of the lytic replication cascade of KSHV. We have now assessed the ability of a novel Pim kinase inhibitor to restore the Nutlin-3-induced cytotoxicity in lytic PEL cells. PEL cells induced to lytic replication by phorbol esters showed 50% inhibition of active viral replication following treatment with the Pim kinase inhibitor. Importantly, co-treatment of these cells with the kinase inhibitor and Nutlin-3 resulted in a robust restoration of the Nutlin-3-induced cell death. These results highlight the potential impact of activation of viral lytic replication on disease progression and response to treatment in KSHV-induced lymphomas.

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Acknowledgements

We thank M Laiho for reagents, discussions and critical review of this manuscript; C Boshoff for valuable comments; E Cesarman for providing the BC-3/NF-κB-luc cell line; D Ganem for anti-RTA antibody; and B Chandran for anti-ORF59 and anti-LANA antibodies. J Bärlund, S Vartia and P Kivinen are acknowledged for excellent technical assistance. This work was supported by grants from the Academy of Finland (PMO, PL), Finnish Cancer Foundations (PMO, PL), Sigrid Juselius Foundation (PMO), University of Helsinki Foundations (PMO), and from the European Union (FP6 INCA project LSHC-CT-2005-018704) to PMO, AJ, GS and LM were supported by the University of Helsinki Graduate Program in Biotechnology and Molecular Biology. JE was supported by the Helsinki Biomedical Graduate School. GS was also supported by Finnish Cultural Foundation, Paulo Foundation, K Albin Johansson Foundation, Maud Kuistila Memorial Foundation, University of Helsinki Funds and Biomedicum Helsinki Foundation.

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Authors and Affiliations

  1. Institute of Biotechnology & Research Programs Unit, Genome-Scale-Biology, Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

    G Sarek, L Ma & P M Ojala

  2. Research Programs Unit, Molecular Cancer Biology, Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

    J Enbäck & P Laakkonen

  3. Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland

    A Järviluoma

  4. Clermont Université, Université Blaise Pascal, SEESIB, Clermont-Ferrand, CNRS, Aubière, France

    P Moreau

  5. Divison of Pathway Medicine, School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK

    J Haas

  6. Max-von-Pettenkofer Institute, University of Munich, Munich, Germany

    J Haas

  7. Département de Virologie, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Bâtiment Lwoff, Institut Pasteur, Paris, France

    A Gessain

  8. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

    P J Koskinen

  9. K Albin Johansson Foundation, Helsinki, Finland

    P Laakkonen

  10. Finnish Cancer Institute, Helsinki, Finland

    P M Ojala

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Sarek, G., Ma, L., Enbäck, J. et al. Kaposi's sarcoma herpesvirus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas. Oncogene 32, 1091–1098 (2013). https://doi.org/10.1038/onc.2012.118

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