Abstract
Newcastle disease virus (NDV) has a potential oncolytic effect due to its ability to induce apoptosis in tumor cells. However, previous studies have indicated discrepancies regarding the apoptosis signaling pathways induced by NDV in tumor cells. Here, we show that NDV infection induces simultaneous activation of intrinsic and extrinsic death pathways in A549 human lung cancer cells. In contrast, endoplasmic reticulum (ER) stress is not activated in NDV-induced apoptosis. We demonstrate for the first time that mitogen-activated protein kinase (MAPK) pathways are activated in NDV-infected A549 cells, and p38 MAPK is involved in NDV-induced cell death. Together, our findings provide novel insights into the underlying mechanisms by which NDV induces apoptosis in tumor cells.
Similar content being viewed by others
References
Batliwalla FM, Bateman BA, Serrano D, Murray D, Macphail S, Maino VC, Ansel JC, Gregersen PK, Armstrong CA (1998) A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4:783–794
Brugh M, Beard CW (1984) Atypical disease produced in chickens by Newcastle disease virus isolated from exotic birds. Avian Dis 28:482–488
Cassel WA, Garrett RE (1965) Newcastle disease virus as an antineoplastic agent. Cancer 18:863–868
Csatary LK, Moss RW, Beuth J, Torocsik B, Szeberenyi J, Bakacs T (1999) Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19:635–638
Dortmans JC, Rottier PJ, Koch G, Peeters BP (2010) The viral replication complex is associated with the virulence of Newcastle disease virus. J Virol 84:10113–10120
Ekert PG, Vaux DL (1997) Apoptosis and the immune system. Br Med Bull 53:591–603
Elankumaran S, Rockemann D, Samal SK (2006) Newcastle disease virus exerts oncolysis by both intrinsic and extrinsic caspase-dependent pathways of cell death. J Virol 80:7522–7534
Elankumaran S, Chavan V, Qiao D, Shobana R, Moorkanat G, Biswas M, Samal SK (2010) Type I interferon-sensitive recombinant Newcastle disease virus for oncolytic virotherapy. J Virol 84:3835–3844
Fabian Z, Csatary CM, Szeberenyi J, Csatary LK (2007) p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. J Virol 81:2817–2830
Fiola C, Peeters B, Fournier P, Arnold A, Bucur M, Schirrmacher V (2006) Tumor selective replication of Newcastle disease virus: association with defects of tumor cells in antiviral defence. Int J Cancer 119:328–338
Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Rasooly L, Greenbaum E, Rozenman-Yair S, Panet A, Libson E, Irving CS, Galun E, Siegal T (2006) Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 13:221–228
Jiang X, Wang X (2004) Cytochrome C-mediated apoptosis. Annu Rev Biochem 73:87–106
Krishnamurthy S, Takimoto T, Scroggs RA, Portner A (2006) Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines. J Virol 80:5145–5155
Lazar I, Yaacov B, Shiloach T, Eliahoo E, Kadouri L, Lotem M, Perlman R, Zakay-Rones Z, Panet A, Ben-Yehuda D (2010) The oncolytic activity of Newcastle disease virus NDV-HUJ on chemoresistant primary melanoma cells is dependent on the proapoptotic activity of the inhibitor of apoptosis protein Livin. J Virol 84:639–646
Luo H, Yanagawa B, Zhang J, Luo Z, Zhang M, Esfandiarei M, Carthy C, Wilson JE, Yang D, McManus BM (2002) Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. J Virol 76:3365–3373
Meng S, Bai H, Hu M, Liu W, Wang L, Wu Y, Jiao X, Fan J (2009) Mechanisms of in vitro anti-tumor effects of a Newcastle disease virus. Wei Sheng Wu Xue Bao 49:512–517
Meng S, Gui Q, Xu Q, Lu K, Jiao X, Fan J, Ge B, Ke Y, Zhang S, Wu J, Wang C (2010) Association of Shp2 with phosphorylated IL-22R1 is required for interleukin-22-induced MAP kinase activation. J Mol Cell Biol 2:223–230
Momoi T (2004) Caspases involved in ER stress-mediated cell death. J Chem Neuroanat 28:101–105
Nagai Y (1999) Paramyxovirus replication and pathogenesis. Reverse genetics transforms understanding. Rev Med Virol 9:83–99
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103
Pecora AL, Rizvi N, Cohen GI, Meropol NJ, Sterman D, Marshall JL, Goldberg S, Gross P, O’Neil JD, Groene WS, Roberts MS, Rabin H, Bamat MK, Lorence RM (2002) Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20:2251–2266
Pfirschke C, Schirrmacher V (2009) Cross-infection of tumor cells by contact with T lymphocytes loaded with Newcastle disease virus. Int J Oncol 34:951–962
Puhlmann J, Puehler F, Mumberg D, Boukamp P, Beier R (2010) Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus. Oncogene 29:2205–2216
Rathmell JC, Thompson CB (1999) The central effectors of cell death in the immune system. Annu Rev Immunol 17:781–828
Ravindra PV, Tiwari AK, Ratta B, Chaturvedi U, Palia SK, Chauhan RS (2009) Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis. Virus Res 141:13–20
Reddy KB, Nabha SM, Atanaskova N (2003) Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22:395–403
Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter RJ, Fernando MB, Reyes HM, Greager JA (1992) Newcastle disease virus selectively kills human tumor cells. J Surg Res 52:448–453
Schirrmacher V, Haas C, Bonifer R, Ahlert T, Gerhards R, Ertel C (1999) Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6:63–73
Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63
Si X, Luo H, Morgan A, Zhang J, Wong J, Yuan J, Esfandiarei M, Gao G, Cheung C, McManus BM (2005) Stress-activated protein kinases are involved in coxsackievirus B3 viral progeny release. J Virol 79:13875–13881
Sinkovics JG, Horvath JC (2000) Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16:1–15
Stiles BL (2009) PI-3-K and AKT: onto the mitochondria. Adv Drug Deliv Rev 61:1276–1282
Sumbayev VV, Yasinska IM (2006) Role of MAP kinase-dependent apoptotic pathway in innate immune responses and viral infection. Scand J Immunol 63:391–400
Szeberenyi J, Fabian Z, Torocsik B, Kiss K, Csatary LK (2003) Newcastle disease virus-induced apoptosis in PC12 pheochromocytoma cells. Am J Ther 10:282–288
Weaver BK, Ando O, Kumar KP, Reich NC (2001) Apoptosis is promoted by the dsRNA-activated factor (DRAF1) during viral infection independent of the action of interferon or p53. FASEB J 15:501–515
Wheelock EF, Dingle JH (1964) Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271:645–651
Wise MG, Suarez DL, Seal BS, Pedersen JC, Senne DA, King DJ, Kapczynski DR, Spackman E (2004) Development of a real-time reverse-transcription PCR for detection of Newcastle disease virus RNA in clinical samples. J Clin Microbiol 42:329–338
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331
Yaacov B, Eliahoo E, Lazar I, Ben-Shlomo M, Greenbaum I, Panet A, Zakay-Rones Z (2008) Selective oncolytic effect of an attenuated Newcastle disease virus (NDV-HUJ) in lung tumors. Cancer Gene Ther 15:795–807
Yang TC, Shiu SL, Chuang PH, Lin YJ, Wan L, Lan YC, Lin CW (2009) Japanese encephalitis virus NS2B-NS3 protease induces caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells. Virus Res 143:77–85
Acknowledgments
We are grateful to Prof. Bu Zhigao and Dr. Jia Lijun for helpful discussions. This work was supported by grants from National Key Laboratory of Veterinary Biotechnology of China (SKLVBF200903), Earmarked Fund for Modern Agro-industry Technology Research System, Department of Science and Technology of Zhejiang Province (2009R100310) and Natural Science Foundation of Zhejiang Province (Y2080323).
Author information
Authors and Affiliations
Corresponding authors
Additional information
J. Bian and K. Wang contributed equally to this work.
Rights and permissions
About this article
Cite this article
Bian, J., Wang, K., Kong, X. et al. Caspase- and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus. Arch Virol 156, 1335–1344 (2011). https://doi.org/10.1007/s00705-011-0987-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-011-0987-y