Skip to main content
SpringerLink
Log in

HN Protein of Newcastle Disease Virus Induces Apoptosis Through SAPK/JNK Pathway

  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Many viral proteins are responsible for causing induction of apoptosis in the target cells. Hemagglutinin neuraminidase (HN), a multifunctional protein of Newcastle disease virus (NDV), is one of such proteins. The present study was undertaken to determine the apoptotic potential of the HN gene in cultured human cervical cancer cell line (HeLa cell) and to elucidate the molecular mechanisms involved. The results of the study indicate that HN protein causes apoptosis in HeLa cells, as observed by the translocation of Phosphatidylserine, activation of caspases, cleavage of poly (ADP-ribose) polymerase (PARP), and DNA fragmentation. Further, we report that expression of HN protein upregulates the SAPK/JNK pathway leading to transactivation of c-Jun which in turn activates apoptosis signaling. The results of our study provide an insight into the mechanism through which HN induces apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Brown, J. M., & Attardi, L. D. (2005). The role of apoptosis in cancer development and treatment response. Nature Review Cancer, 5, 231–237.

    CAS  Google Scholar 

  2. Fischer, V., & Schulze-Osthoff, K. (2005). New approaches and therapeutics targeting apoptosis in disease. Pharmacological Reviews, 57, 187–215.

    Article  CAS  Google Scholar 

  3. Kleinberger, T. (2002). Induction of apoptosis by adeno virus E40rF4 protein. Apoptosis, 5, 211–215.

    Article  Google Scholar 

  4. Rohn, J. L., & Noteborn, M. H. M. (2004). The viral death effector Apoptin reveals tumor-specific processes. Apoptosis, 9(3), 315–322.

    Article  CAS  Google Scholar 

  5. Saxena, L., Gandham, R. K., Saxena, S., Chaturvedi, U., Sahoo, A. P., Singh, L. V., Santra, L., Palia, S. K., Desai, G. S., & Tiwari, A. K. (2013). Apoptosis induced by NS1 gene of Canine Parvovirus-2 is caspase dependent and p53 independent. Virus Research, 173(2), 426–430.

    Article  CAS  Google Scholar 

  6. Santra, L., Rajmani, R. S., Kumar, G. R., Saxena, S., Dhara, S. K., Kumar, A., Sahoo, A. P., Singh, L. V., Desai, G. S., Chaturvedi, U., Kumar, S., & Tiwari, A. K. (2014). Non-structural protein 1 (NS1) gene of canine parvovirus-2 regresses chemically induced skin tumors in Wistar rats. Research in veterinary science, 97(2), 292–296.

  7. Gupta, S. K., Gandham, R. K., Sahoo, A. P., & Tiwari, A. K. (2015). Viral genes as oncolytic agents for cancer therapy. Cellular and Molecular Life Sciences, 72(6), 1073–1094.

    Article  CAS  Google Scholar 

  8. Gupta, S. K., Sahoo, A. P., Gandham, R. K., Rosh N, Saxena L, Singh A, Harish DR, Tiwari, A. K. (2015b). Canine parvovirus NS1 induced apoptosis involves mitochondria, accumulation of reactive oxygen species and activation of caspases.

  9. Reichard, K. W., Lorence, R. M., Cascino, C. J., Peeples, M. E., Walter, R. J., Fernando, M. B., Reyes, H. M., & Greager, J. A. (1992). Newcastle disease virus selectively kills human tumor cells. Journal of Surgical Research, 52(5), 448–453.

    Article  CAS  Google Scholar 

  10. Lorence, R. M., Reichard, K. W., Katubig, B. B., Reyers, H. M., Phuangsab, A., Sasetti, M. D., Walter, R. J., & Peeples, M. E. (1994). Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Research, 54, 6017–6021.

    CAS  Google Scholar 

  11. Phuangsab, A., Lorence, R. M., Reichard, K. W., Peeples, M. E., & Walter, R. J. (2001). Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Letters, 172, 27–36.

    Article  CAS  Google Scholar 

  12. Ravindra, P. V., Tiwari, A. K., Ratta, B., Chaturvedi, U., Palia, S. K., Subudhi, P. K., Kumar, R., Sharma, B., Rai, A., Chauhan, R.S. (2008). Induction of apoptosis in Vero cells by Newcastle disease virus requires viral replication, de-novo protein synthesis and caspase activation. Virus Research, 133(2), 285–290.

  13. Rajmani, R. S., Singh, P. K., Gandha, R. K., Saxena, S., Singh, L. V., Kumar, R., Sahoo, A. P., Gupta, S. K., Chaturvedi, U., & Tiwari, A. K. (2014). In-vitro characterization and evaluation of apoptotic potential of bicistronic plasmid encoding HN gene of Newcastle disease virus and human TNF-a. Animal Biotechnology, 1–8.

  14. Ravindra, P. V., Tiwari, A. K., Sharma, B., Rajawat, Y. S., Ratta, B., Palia, S. K., & Sundaresan, N. R. (2008). HN protein of Newcastle disease virus causes apoptosis in chicken embryo fibroblast cells. Archives of Virology, 153(4), 749–754.

    Article  CAS  Google Scholar 

  15. Sun, Y. C., Jin, N. Y., Mi, Z. Q., Li, X., Lian, H., & Li, P. (2005). Induction of apoptosis in human hepatoma cell line SMMC7721 by Newcastle disease virus HN gene. Zhonghua Zhong liu za zhi [Chinese Journal of Oncology], 27(5), 279–282.

    Google Scholar 

  16. Ghrici, M., El Zowalaty, M., Omar, A. R., & Ideris, A. (2013). Induction of apoptosis in MCF-7 cells by the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus Malaysian strain AF2240. Oncology Reports, 30(3), 1035–1044.

    CAS  Google Scholar 

  17. Ni, J., Galani, I. E., Cerwenka, A., Schirrmacher, V., & Fournier, P. (2011). Antitumor vaccination by Newcastle Disease Virus Hemagglutinin–Neuraminidase plasmid DNA application: changes in tumor microenvironment and activation of innate anti-tumor immunity. Vaccine, 29(6), 1185–1193.

    Article  CAS  Google Scholar 

  18. Lorence, R. M., Rood, P. A., & Kelley, K. W. (1988). Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-α and augmentation of its cytotoxicity2. Journal of the National Cancer Institute, 80(16), 1305–1312.

    Article  CAS  Google Scholar 

  19. Washburn, B., Weigand, M. A., Grosse-Wilde, A., Janke, M., Stahl, H., Rieser, E., Sprick, M. R., Schirrmacher, V., & Walczak, H. (2003). TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus. The Journal of Immunology, 170(4), 1814–1821.

    Article  CAS  Google Scholar 

  20. Zeng, J., Fournier, P., & Schirrmacher, V. (2002). Induction of interferon-α and tumor necrosis factor-related apoptosis-inducing ligand in human blood mononuclear cells by hemagglutinin-neuraminidase but not F protein of Newcastle disease virus. Virology, 297(1), 19–30.

    Article  CAS  Google Scholar 

  21. Caraglia, M., Abbruzzese, A., Leardi, A., Pepe, S., Budillon, A., Baldassare, G., & Selleri, C. (1999). Interferon-alpha induces apoptosis in human KB cells through a stress-dependent mitogen activated protein kinase pathway that is antagonized by epidermal growth factor. Cell Death and Differentiation, 6(8), 773–780.

    Article  CAS  Google Scholar 

  22. Steiner, T., Junker, U., Henzgen, B., Nuske, K., Durum, S. K., & Schubert, J. (2001). Interferon–alpha suppresses the antiapoptotic effect of NF–kB and sensitizes renal cell carcinoma cells in vitro to chemotherapeutic drugs. European Urology, 39(4), 478–483.

    Article  CAS  Google Scholar 

  23. Rath, P. C., & Aggarwal, B. B. (2001). Antiproliferative effects of IFN-α correlate with the downregulation of nuclear factor-κ B in human Burkitt lymphoma Daudi cells. Journal of Interferon & Cytokine Research, 21(7), 523–528.

    Article  CAS  Google Scholar 

  24. Zhang, S., Lin, Z. N., Yang, C. F., Shi, X., Ong, C. N., & Shen, H. M. (2004). Suppressed NF-κB and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-α-induced apoptosis in human cancer cells. Carcinogenesis, 25(11), 2191–2199.

    Article  CAS  Google Scholar 

  25. Panaretakis, T., Hjortsberg, L., Tamm, K. P., Björklund, A. C., Joseph, B., & Grandér, D. (2008). Interferon α induces nucleus-independent apoptosis by activating extracellular signal-regulated kinase 1/2 and c-Jun NH2-terminal kinase downstream of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Molecular Biology of the Cell, 19(1), 41–50.

    Article  CAS  Google Scholar 

  26. Yanase, N., Kanetaka, Y., & Mizuguchi, J. (2007). Interferon-α-induced apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent and-independent manner. Oncology Reports, 18(4), 1031–1038.

    CAS  Google Scholar 

  27. Rajawat, Y. S., Sundaresean, N. R., Ravindra, P. V., Kantaraja, C., Ratta, B., Sudgagar, M., Rai, A., Saxena, V. K., Palia, S. K., & Tiwari, A. K. (2008). Immune responses induced by DNA vaccines encoding Newcastle virus haemagglutinin and/or fusion protein in material antibody- positive commercial broiler chicken. British Poultry Science, 49(2), 111–117.

    Article  CAS  Google Scholar 

  28. Hermann, M., Lorenz, H. M., Voll, R., Grunke, M., Woith, W., & Kalden, J. R. (1994). A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Research, 22, 5506–5507.

    Article  Google Scholar 

  29. Hughes, D., & Mehmet, H. (2003). Cell proliferation and apoptosis, 1st edn (pp. 341–342).

  30. Schwartzman, R. A., & Cidlowski, J. A. (1993). Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocrine Reviews, 14(2), 133–151.

    CAS  Google Scholar 

  31. Fadok, V. A., Voelker, D. R., Campbell, P. A., Cohen, J. J., Bratton, D. L., & Henson, P. M. (1992). Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. The Journal of Immunology, 148(7), 2207–2216.

    CAS  Google Scholar 

  32. Fraker, P. J., King, L. E., Lill-Elghanian, D., & Telford, W. G. (1994). Quantification of apoptotic events in pure and heterogeneous populations of cells using the flow cytometer. Methods in Cell Biology, 46, 57–76.

    Article  Google Scholar 

  33. Knoopman, G., Reutelingsperger, C. P., Kuijten, G. A., Keehnen, R. M., Pals, S. T., & Vanoers, M. H. (1994). Annexin-V for flow cytometric detection of phosphatidylserine expression on B-cells undergoing apoptosis. Blood, 84, 1415–1420.

    Google Scholar 

  34. Gavrieli, Y., Sherman, Y., & Ben-Sasson, S. A. (1992). Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. The Journal of Cell Biology, 119(3), 493–501.

    Article  CAS  Google Scholar 

  35. Sgonc, R., Boeck, G., Dietrich, H.,Gruber, J., Recheis, H., Wick, G. (1994). Simultaneous determination of cell surface antigens and apoptosis. Trends in Genetics. 10, 41–42.

  36. Sgonc, R., Gruschwitz, M. S., Dietrich, H., Gershwin, M. E., & Wick, G. (1996). Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. Journal of Clinical Investigations, 98, 785–792.

    Article  CAS  Google Scholar 

  37. Budihardjo, I., Oliver, H., Lutter, M., Luo, X., & Wang, X. (1999). Biochemical pathways of caspase activation during apoptosis. Annual Review of Cell Developmental Biology, 15, 269–290.

    Article  CAS  Google Scholar 

  38. Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. British Journal of Cancer, 26, 239–257.

    Article  CAS  Google Scholar 

  39. Hamid, A. B., Alexander, G. Y., Vessela, I., Bogdan, A. S., Geping, W., Sudha, I., & Mark, S. (1999). Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis caspases-3 resistant PARP mutant increases rates of apoptosis in transfected cells. The Journal of Biological Chemistry, 274(33), 22932–22940.

    Article  Google Scholar 

  40. Drew, Y., & Plummer, R. (2009). PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resistance Updates, 12 (6), 153 6

  41. Hong, Sui., Yuxian, Bai., Kaibling, Wang., Xi, Li., Chun, Song., Fang, Fu., Zhang, Y., Lejing, Li. (2010). The anti-tumor effect of Newcastle disease virus HN protein is influenced by differential subcellular targeting. Cancer Immunology and Immunotherapy, 59, 989–999.

  42. Elankumaran, S., Rockemann, D., & Samal, S. K. (2006). Newcastle disease virus exerts oncolysis by both intrinsic and extrinsic caspase-dependent pathways of cell death. Journal of Virology, 80(15), 7522–7534.

    Article  CAS  Google Scholar 

  43. Ravindra, P. V., Tiwari, A. K., Ratta, B., Chaturvedi, U., Palia, S. K., & Chauhan, R. S. (2009). Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis. Virus Research, 141, 13–20.

    Article  CAS  Google Scholar 

  44. Molouki, A., Hsu, Y. T., Jahanshiri, F., Rosli, R., & Yusoff, K. (2010). Newcastle disease virus infection promotes Bax redistribution to mitochondria and cell death in HeLa cells. Intervirology, 53(2), 87–94.

    Article  Google Scholar 

  45. Molouki, A., & Yusoff, K. (2012). NDV-induced apoptosis in absence of Bax; evidence of involvement of apoptotic proteins upstream of mitochondria. Virology Journal, 9, 179.

    Article  CAS  Google Scholar 

  46. Dhanasekaran, N., & Reddy, E. P. (1998). Signaling by dual specificity kinases. Oncogene, 17(11), 1447–1455.

    Article  CAS  Google Scholar 

  47. Chauhan, D., Li, G., Hideshima, T., Podar, K., Mitsiades, C., Mitsiades, N., & Anderson, K. C. (2003). JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. Journal of Biological Chemistry, 278(20), 17593–17596.

    Article  CAS  Google Scholar 

  48. Deng, Y., Ren, X., Yang, L., Lin, Y., & Wu, X. (2003). A JNK-dependent pathway is required for TNFα-induced apoptosis. Cell, 115(1), 61–70.

    Article  CAS  Google Scholar 

  49. Fan, H., Xiao, S., & Tong, T. (2008). Immunogenicity of porcine circovirus type 2 capsid protein targeting to different subcellular compartments. Molecular Immunology, 45, 653–660.

    Article  CAS  Google Scholar 

  50. Noriko, Y., Kikumi, H., Kuniaki, S., Miho, H., Mark, B., & Junichiro, M. (2005). Requirement of c-Jun NH2-terminal kinase activation in interferon-α-induced apoptosis through upregulation of tumor necrosis factor-related apoptosis-inducing ligands (TRAIL) in Daudin B lymphoma cells. Experimental Cell Research, 310, 10–21.

    Article  Google Scholar 

  51. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., & Karin, M. (2005). Reactive oxygen species promote TNF-alpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell, 120, 649–661.

    Article  CAS  Google Scholar 

  52. Lin, A., & Dibling, B. (2002). The true face of JNK activation in apoptosis. Aging Cell, 1, 112–116.

    Article  CAS  Google Scholar 

  53. Gigante, M., Mandic, M., Wesa, A. K., Cavalcanti, E., Dambrosio, M., & Mancini, V. (2008). Interferon-alpha (IFN-alpha)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients. Journal of Immunotherapy, 31(3), 254–262.

    Article  CAS  Google Scholar 

  54. Fournier, P., Arnold, A., & Schirrmacher, V. (2009). Polarization of human monocyte-derived dendritic cells to DC1 by in vitro stimulation with Newcastle Disease Virus. Journal of BUON, 14, S111–S122.

    Google Scholar 

Download references

Acknowledgments

The authors are thankful to the Director, Indian Veterinary Research Institute, Izatnagar-243122, UP, India, for providing necessary facilities and the National Agricultural Innovative Project (reference C4/C3001) for providing funding to carry out the work.

Conflict of interest

The authors declare they have no competing interests.

Author information

Authors and Affiliations

  1. Molecular Biology Laboratory, Division of Veterinary Biotechnology, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, 243122, India

    R. S. Rajmani, Ravi Kumar Gandham, Shishir Kumar Gupta, A. P. Sahoo, Prafull Kumar Singh, Rajiv Kumar, Shikha Saxena, Uttara Chaturvedi & Ashok K. Tiwari

Authors
  1. R. S. Rajmani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravi Kumar Gandham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shishir Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. P. Sahoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Prafull Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rajiv Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shikha Saxena
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Uttara Chaturvedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ashok K. Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashok K. Tiwari.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajmani, R.S., Gandham, R.K., Gupta, S.K. et al. HN Protein of Newcastle Disease Virus Induces Apoptosis Through SAPK/JNK Pathway. Appl Biochem Biotechnol 177, 940–956 (2015). https://doi.org/10.1007/s12010-015-1788-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-015-1788-7

Keywords

Search

Navigation