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Multi-targeted therapy of everolimus in Kaposi’s sarcoma associated herpes virus infected primary effusion lymphoma

Apoptosis volume 22, pages 1098–1115 (2017)Cite this article

Abstract

Kaposi’s sarcoma associated herpes virus (KSHV) infected primary effusion lymphoma (PEL) is a rare aggressive form of non-Hodgkin’s lymphoma of B cells. KSHV latent and lytic antigens modulate several host cellular signalling pathways especially mammalian target of rapamycin (mTOR), STAT-3 and nuclear factor-kappa B (NF-κB) for rapid tumor progression and immune evasion. Current chemotherapeutic strategies are becoming ineffective as they kill only dividing cells and inefficient to target molecular pathways crucial for active virus replication and its survival. In this study, we evaluated the efficacy of everolimus, an mTOR inhibitor in inducing apoptosis of PEL cells. Dose-dependent treatment of everolimus triggered mitochondria-mediated caspase-dependent apoptosis in PEL cells. Everolimus downregulated KSHV latent antigen expression with concurrent blocking of lytic reactivation for active virus replication. Everolimus also inhibited latent antigen mediated constitutively active STAT-3 and NF-κB signalling. We co-cultured everolimus treated PEL cells with immature dendritic cells and found activation of dendritic cells with increase in surface expression of CD86 and HLA-DR. As everolimus targets and disrupts KSHV antigens as well as antigen facilitated multiple signalling pathways necessary for KSHV survival and maintenance of infection with synchronised boosting of immune system against viral infection, it can be a better therapeutic approach towards treatment of PEL.

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Abbreviations

KSHV:

Kaposi’s sarcoma associated herpes virus

PEL:

Primary effusion lymphoma

HIV:

Human immunodeficiency virus

HPV:

Human papillomavirus

EBV:

Epstein bar virus

KS:

Kaposi sarcoma

NF-κB:

Nuclear factor kappa B

STAT-3:

Signal transducer and activator of transcription-3

LANA:

Latency associated nuclear antigen

vFLIP:

Viral FLICE inhibitory protein

PI3K:

Phosphoinositide-3-kinase

RTA:

Replication transcriptional activator

EBV:

Epstein bar virus

IKK:

I kappa B kinase

PI:

Propidium iodide

iDC:

Immature dendritic cells

LC3 II:

Light chain 3 type II

TPA:

Phorbol 12-tetradecanoate 13-acetate

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Acknowledgements

This work was supported by the Extramural fund of Department of Biotechnology (BT/PR7044/MED/29/855/2014), Govt. of India DBT and University Grant Commission (UGC-Major-Project-43-83/2014(SR)). We are grateful to Prof. David J Blackbourn, University of Surrey, for the kind gift of JSC-1 cell line and Prof. Erle S Robertson, the University of Pennsylvania for providing BC-3 and BJAB cells. We also like to thank Dr. Ratnadeep Mukherjee for his help in manuscript preparation. We also appreciate the assistance of Mr. Manas Ranjan Sarangi for various experimental procedures and Mr. Paritosh Nath for his support in flow cytometry experiments.

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Affiliations

  1. Division of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India

    Suchitra Mohanty, Amit Kumar & Sushil Kumar Sahu

  2. Department of Biotechnology, Siksha Bhabana, Visva Bharati, Santiniketan, Bolpur, India

    Piyanki Das & Tathagata Choudhuri

Authors
  1. Suchitra Mohanty
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  2. Amit Kumar
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  3. Piyanki Das
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  4. Sushil Kumar Sahu
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  5. Tathagata Choudhuri
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Contributions

SM, TC: Conceived and designed the experiments. SM, AK: Performed the experiments. SM, AK SKS, TC: Analyzed the data. TC: Contributed reagents/materials/analysis tools. PD: Revision Experiments according to reviewers comments. SM, TC: Wrote the paper.

Corresponding author

Correspondence to Tathagata Choudhuri.

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The authors have declared no conflict of interest.

Ethical approval

The present study was approved by the Human Ethics Committee of “Institute of Life Sciences”, Bhubaneswar, India in accordance with the approved guidelines. Blood samples were collected after obtaining informed consent of the healthy controls.

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Mohanty, S., Kumar, A., Das, P. et al. Multi-targeted therapy of everolimus in Kaposi’s sarcoma associated herpes virus infected primary effusion lymphoma. Apoptosis 22, 1098–1115 (2017). https://doi.org/10.1007/s10495-017-1391-1

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Keywords

  • KSHV
  • Primary effusion lymphoma
  • Apoptosis
  • Autophagy
  • NF-κB
  • STAT-3