Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy

Oncogene volume 29, pages 5630–5642 (2010)Cite this article

Subjects

Abstract

Neuroblastomas are pediatric tumors that develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1–Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. As both processes are Y2R-mediated, the aim of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 mitogen-activated protein kinase (MAPK) induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY small interfering RNA (siRNA) and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TdT-mediated dUTP nick end labeling; TUNEL). The Y2R antagonist also exerted an antiangiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Biedler JL, Roffler-Tarlov S, Schachner M, Freedman LS . (1978). Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res 38: 3751–3757.

    CAS  PubMed  Google Scholar 

  • Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M et al. (2008). Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455: 971–974.

    Article  CAS  PubMed  Google Scholar 

  • Cohen PS, Cooper MJ, Helman LJ, Thiele CJ, Seeger RC, Israel MA . (1990). Neuropeptide Y expression in the developing adrenal gland and in childhood neuroblastoma tumors. Cancer Res 50: 6055–6061.

    CAS  PubMed  Google Scholar 

  • Dotsch J, Christiansen H, Hanze J, Lampert F, Rascher W . (1998). Plasma neuropeptide Y of children with neuroblastoma in relation to stage, age and prognosis, and tissue neuropeptide Y. Regul Pept 75-76: 185–190.

    Article  CAS  PubMed  Google Scholar 

  • Ekstrand AJ, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander AC, Hassani H et al. (2003). Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci USA 100: 6033–6038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • George RE, Sanda T, Hanna M, Frohling S, Luther II W, Zhang J et al. (2008). Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455: 975–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansel DE, Eipper BA, Ronnett GV . (2001). Neuropeptide Y functions as a neuroproliferative factor. Nature 410: 940–944.

    Article  CAS  PubMed  Google Scholar 

  • Jonsson-Rylander AC, Nordlander M, Svindland A, Ilebekk A . (2003). Distribution of neuropeptide Y Y1 and Y2 receptors in the postmortem human heart. Peptides 24: 255–262.

    Article  CAS  PubMed  Google Scholar 

  • Kitlinska J, Abe K, Kuo L, Pons J, Yu M, Li L et al. (2005). Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res 65: 1719–1728.

    Article  CAS  PubMed  Google Scholar 

  • Kitlinska J, Lee EW, Movafagh S, Pons J, Zukowska Z . (2002). Neuropeptide Y-induced angiogenesis in aging. Peptides 23: 71–77.

    Article  CAS  PubMed  Google Scholar 

  • Kogner P, Bjork O, Theodorsson E . (1994). Plasma neuropeptide Y in healthy children: influence of age, anaesthesia and the establishment of an age-adjusted reference interval. Acta Paediatr 83: 423–427.

    Article  CAS  PubMed  Google Scholar 

  • Korner M, Waser B, Reubi JC . (2004). High expression of neuropeptide Y receptors in tumors of the human adrenal gland and extra-adrenal paraganglia. Clin Cancer Res 10: 8426–8433.

    Article  PubMed  Google Scholar 

  • Koulu M, Movafagh S, Tuohimaa J, Jaakkola U, Kallio J, Pesonen U et al. (2004). Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization. Ann Med 36: 232–240.

    Article  CAS  PubMed  Google Scholar 

  • Lee EW, Grant DS, Movafagh S, Zukowska Z . (2003a). Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice. Peptides 24: 99–106.

    Article  CAS  PubMed  Google Scholar 

  • Lee EW, Michalkiewicz M, Kitlinska J, Kalezic I, Switalska H, Yoo P et al. (2003b). Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest 111: 1853–1862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lei K, Davis RJ . (2003). JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100: 2432–2437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ . (2003). Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 278: 18811–18816.

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Zhang J, Liu Z, Woo CW, Thiele CJ . (2007). Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ 14: 318–326.

    Article  PubMed  Google Scholar 

  • Magni P, Beretta E, Scaccianoce E, Motta M . (2000). Retinoic acid negatively regulates neuropeptide Y expression in human neuroblastoma cells. Neuropharmacology 39: 1628–1636.

    Article  CAS  PubMed  Google Scholar 

  • Malmstrom RE . (2001). Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y(2) receptor antagonist, in vivo. Br J Pharmacol 133: 1073–1080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maris JM . (2005). The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 17: 7–13.

    Article  PubMed  Google Scholar 

  • Maris JM, Hogarty MD, Bagatell R, Cohn SL . (2007). Neuroblastoma. Lancet 369: 2106–2120.

    Article  CAS  PubMed  Google Scholar 

  • Meitar D, Crawford SE, Rademaker AW, Cohn SL . (1996). Tumor angiogenesis correlates with metastatic disease, N-myc amplification, and poor outcome in human neuroblastoma. J Clin Oncol 14: 405–414.

    Article  CAS  PubMed  Google Scholar 

  • Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF et al. (2008). Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455: 930–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Movafagh S, Hobson JP, Spiegel S, Kleinman HK, Zukowska Z . (2006). Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J 20: 1924–1926.

    Article  CAS  PubMed  Google Scholar 

  • Naveilhan P, Hassani H, Canals JM, Ekstrand AJ, Larefalk A, Chhajlani V et al. (1999). Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nat Med 5: 1188–1193.

    Article  CAS  PubMed  Google Scholar 

  • O'Hare MM, Schwartz TW . (1989a). Expression and precursor processing of neuropeptide Y in human and murine neuroblastoma and pheochromocytoma cell lines. Cancer Res 49: 7015–7019.

    CAS  PubMed  Google Scholar 

  • O'Hare MM, Schwartz TW . (1989b). Expression and precursor processing of neuropeptide Y in human pheochromocytoma and neuroblastoma tumors. Cancer Res 49: 7010–7014.

    CAS  PubMed  Google Scholar 

  • Park JR, Eggert A, Caron H . (2008). Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin N Am 55: 97–120.

    Article  Google Scholar 

  • Pons J, Kitlinska J, Jacques D, Perreault C, Nader M, Everhart L et al. (2008). Interactions of multiple signaling pathways in neuropeptide Y-mediated bimodal vascular smooth muscle cell growth. Can J Physiol Pharmacol 86: 438–448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pons J, Kitlinska J, Ji H, Lee EW, Zukowska Z . (2003). Mitogenic actions of neuropeptide Y in vascular smooth muscle cells: synergetic interactions with the beta-adrenergic system. Can J Physiol Pharmacol 81: 177–185.

    Article  CAS  PubMed  Google Scholar 

  • Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B et al. (2003). JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38: 899–914.

    Article  CAS  PubMed  Google Scholar 

  • Ribatti D, Ponzoni M . (2005). Antiangiogenic strategies in neuroblastoma. Cancer Treat Rev 31: 27–34.

    Article  CAS  PubMed  Google Scholar 

  • Rossler J, Taylor M, Geoerger B, Farace F, Lagodny J, Peschka-Suss R et al. (2008). Angiogenesis as a target in neuroblastoma. Eur J Cancer 44: 1645–1656.

    Article  PubMed  Google Scholar 

  • Sheriff S, Dayal R, Kasckow J, Regmi A, Chance W, Fischer J et al. (1998). NPY upregulates genes containing cyclic AMP response element in human neuroblastoma cell lines bearing Y1 and Y2 receptors: involvement of CREB. Regul Pept 75-76: 309–318.

    Article  CAS  PubMed  Google Scholar 

  • Shusterman S, Maris JM . (2005). Prospects for therapeutic inhibition of neuroblastoma angiogenesis. Cancer Lett 228: 171–179.

    Article  CAS  PubMed  Google Scholar 

  • Uddman R, Moller S, Nilsson T, Nystrom S, Ekstrand J, Edvinsson L . (2002). Neuropeptide Y Y1 and neuropeptide Y Y2 receptors in human cardiovascular tissues. Peptides 23: 927–934.

    Article  CAS  PubMed  Google Scholar 

  • Wassberg E . (1999). Angiostatic treatment of neuroblastoma. Ups J Med Sci 104: 1–24.

    Article  CAS  PubMed  Google Scholar 

  • Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J . (2001). Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29: 629–643.

    Article  CAS  PubMed  Google Scholar 

  • Yoon HZ, Yan Y, Geng Y, Higgins RD . (2002). Neuropeptide Y expression in a mouse model of oxygen-induced retinopathy. Clin Experiment Ophthalmol 30: 424–429.

    Article  PubMed  Google Scholar 

  • Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H et al. (1998). Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83: 187–195.

    Article  CAS  PubMed  Google Scholar 

  • Zukowska-Grojec Z, Pruszczyk P, Colton C, Yao J, Shen GH, Myers AK et al. (1993). Mitogenic effect of neuropeptide Y in rat vascular smooth muscle cells. Peptides 14: 263–268.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH Grant 1R01CA123211-01 and funding from Children's Cancer Foundation (Baltimore, MD, USA) to Joanna Kitlinska. The authors would like to thank John Styliaris and David Hur for help in performing experiments. We also thank the Flow Cytometry/Cell Sorting Shared Resources of Lombardi Comprehensive Cancer Center for technical assistance and Children's Oncology Group for providing human samples.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Georgetown University, Washington, DC, USA

    C Lu, L Everhart, J Tilan, L Kuo, A Kuan-Celarier, L Li, Z Zukowska & J Kitlinska

  2. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

    C-C J Sun

  3. Division of Transplantation, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    R B Munivenkatappa

  4. Bioscience Department, AstraZeneca, Mölndal, Sweden

    A-C Jönsson-Rylander

  5. Department of Critical care medicine, National Institutes of Health, Bethesda, MD, USA

    J Sun

  6. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    K Abe

  7. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    J A Toretsky

Authors
  1. C Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Everhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Tilan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C-C J Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R B Munivenkatappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A-C Jönsson-Rylander
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Kuan-Celarier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Z Zukowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J A Toretsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J Kitlinska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Kitlinska.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, C., Everhart, L., Tilan, J. et al. Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy. Oncogene 29, 5630–5642 (2010). https://doi.org/10.1038/onc.2010.301

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.301

Keywords

This article is cited by

Search

Advanced search

Quick links