Abstract
Hemagglutinin neuraminidase (HN) is a membrane protein of Newcastle disease virus (NDV) with the ability to induce apoptosis in many transformed cell lines. TNF-α is a multi-factorial protein that regulates cell survival, differentiation and apoptosis. In a previous study, we reported that HN protein induces apoptosis by downregulating NF-κB expression. Further, we speculated that downregulation of NF-κB expression might sensitize HeLa cells to TNF-α-mediated apoptosis. Therefore, the present study was undertaken to investigate if HN protein could sensitize HeLa cells to TNF-α and to examine the apoptotic potential of the HN protein and TNF-α in combination. The results revealed that the pro-apoptotic effects were more pronounced with the combination of HN and TNF-α than with HN or TNF-α alone, which indicates that the HN protein indeed sensitized the HeLa cells to TNF-α-induced cell death. The results of the study provide a mechanistic insight into the apoptotic action of HN protein along with TNF-α, which could be valuable in treating tumor types that are naturally resistant to TNF-α.
Similar content being viewed by others
References
Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5(3):231–237
Karin M (2006) NF-κB in cancer development and progression. Nature 441:431–436
Naugler WE, Karin M (2008) NF-κB and cancer identifying targets and mechanisms. Curr Opin Genet Dev 18:19–26
Sarkar FH, Li Y (2008) NF-κB : a potential target for cancer chemoprevention and therapy. Front Biosci 13:2970–2979
Muthumani K, Choo AY, Hwang DS, Ugen KE, Weiner DB (2004) HIV- 1Vpr: enhancing sensitivity of tumors to apoptosis. Curr Drug Deliv 1:335–344
Heilman DW, Green MR, Teodoro JG (2005) The anaphase promoting complex: a critical target for viral proteins and anticancer drugs. Cell Cycle 4:560–563
Singh PK, Doley J, Kumar GR, Sahoo AP, Tiwari AK (2012) Oncolytic viruses & their specific targeting to tumour cells. Ind J Med Res 136:571–584
Gupta SK, Gandham RK, Sahoo AP, Tiwari AK (2015) Viral genes as oncolytic agents for cancer therapy. Cell Mol Life Sci 72(6):1073–1094
Gupta SK, Sahoo AP, Gandham RK, Rosh N, Saxena L, Singh A, Harish DR, Tiwari AK (2016) Canine parvovirus NS1 induced apoptosis involves mitochondria, accumulation of reactive oxygen species and activation of caspases. Virus Res. doi:10.1016/j.virusres.2015.10.019
Gupta SK, Yadav PK, Gandham RK, Sahoo AP, Singh A, Harish DR, Tiwari AK (2016) Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model. Virus Res. doi:10.1016/j.virusres.2015.12.017
Sun YC, Jin NY, Mi ZQ, Li X, Lian Li P (2005) Induction of apoptosis in human hepatoma cell line SMMC77221 by Newcastle disease virus HN gene. Zhonghua Zhong Liu Za Zhi 27(5):279–282
Sui Hong, Bai Yuxian, Wang Kaibling, Li Xi, Song Chun, Fang Fu, Zhang Yongxin, Li Lejing (2010) The anti-tumor effect of Newcastle disease virus HN protein is influenced by differential subcellular targeting. Can Immunol Immunothera 59:989–999
Rajmani RS, Kumar GR, Gupta SK, Sahoo AP, Singh PK, Kumar R, Saxena S, Chaturvedi U, Tiwari AK (2015) HN protein of Newcastle disease virus induces apoptosis through SAPK/JNK pathway. App Biochem Biotechnol. doi:10.1007/s12010-015-1788-7
Ravindra PV, Tiwari AK, Sharma B, Rajawat YS, Ratta B, Palia SK, Sundaresan NR (2008) HN protein of Newcastle disease virus causes apoptosis in chicken embryo fibroblast cells. Arch Virol 153(4):749–754
Ghrici M, El Zowalaty M, Omar AR, Ideris A (2013) Induction of apoptosis in MCF-7 cells by the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus Malaysian strain AF2240. Oncol Rep 30(3):1035–1044
Ni J, Galani IE, 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
Dranoff G (2005) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22
Brzofsky JA, Terabe M, Sangkon O, Belyakov IM, Ahiers JD, Janik JE, Morris JC (2004) Progress on new vaccines strategies for the immunotherapy and prevention of cancer. J Clin Invest 113:1555
Simone M, Carlo RR, Pierluigi P, Donato N (2005) Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 16:35–53
Franco DL, Nojek IM, Molinero L, Coso OA, Costas MA (2002) Osmotic stress sensitizes naturally resistant cells to TNF-α-induced apoptosis. Cell Death Differ 9:1090–1098
Rajmani RS, Singh PK, Kumar GR, Saxena S, Singh LV, Kumar R, Sahoo AP, Gupta SK, Chaturvedi U, Tiwari AK (2014) In-vitro characterization and evaluation of apoptotic potential of bicistronic plasmid encoding HN gene of Newcastle disease virus and human tNF-α. Anim Biotechnol 0:1–8
Zeng J, Fournier P, Schirrmacher V (2002) Induction of interferon-alpha and tumor necrosis factor-related apoptosis-inducing ligand in human blood mononuclear cells by hemagglutininneuraminidase but not F protein of Newcastle disease virus. Virology 297:19–3023
Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34:9–19
Perkins ND (2012) The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Can 12:121–132
Lin A, Dibling B (2002) The true face of JNK activation in apoptosis. Aging Cell 1:112–116
Suk Kyoungho, Kim Yun-Hee, Chang Inik, Kim Ja Young, Choi Yun-Hee, Lee Kye Young, Lee Myung-Shik (2001) IFN-α sensitizes ME-180 human cervical cancer cells to TNF-α induced apoptosis by inhibiting cytoprotective NF-κB activation. FEBS Lett 495:66–70
Steiner T, Junker U, Henzgen B, Nuske K, Durum SK, Schubert J (2001) Interferon-alpha suppresses the anti-apoptotic effect of NF-kB and sensitizes renal cell carcinoma cells in vitro to chemotherapeutic drugs. Eur Urol 39(4):478–483
Pramod CR, Aggarwal BB (2001) Antiproliferative effects of IFN-α correlate with the downregulation of nuclear factor-κ B in human Burkitt lymphoma Daudi cells. J Interf Cytokine Res 21(7):523–528
Naomoto Y, Tanaka N, Fuchimoto S, Orita K (1987) In vitro synergistic effects of natural human tumor necrosis factor and natural human interferon-α. Jpn J Can Res 78:87–92
Kimura M, Haisa M, Uetsuka H, Takaoka M, Ohkawa T, Kawashima R, Yamatsuji T, Gunduz M, Kaneda Y, Tanaka N, Naomoto Y (2003) TNF combined with IFN-α accelerates NF-κB-mediated apoptosis through enhancement of Fas expression in colon cancer cells. Cell Death Differ 10:718–728
Acknowledgments
We are thankful to the director, Indian Veterinary Research Institute, Izatnagar, for providing necessary facilities.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Department of Science and Technology (DST), Government (grant no. SR/SO/AS-0062/2007).
Ethical approval
All applicable national and institutional guidelines for the care and use of animals were followed.
Conflict of interest statement
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Rajmani, R.S., Gupta, S.K., Singh, P.K. et al. HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression. Arch Virol 161, 2395–2405 (2016). https://doi.org/10.1007/s00705-016-2923-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-016-2923-7