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Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance

Oncogene volume 34, pages 3131–3143 (2015)Cite this article

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Abstract

Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous phenotypes. Although low-stage tumors carry a favorable prognosis, >50% of high-risk NB relapses after treatment with a fatal outcome. Thus developing therapies targeting refractory NB remains an unsolved clinical problem. Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to protect NB cells from chemotherapy-induced cell death, while neuropeptide Y (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and angiogenic factor crucial for maintaining NB tumor growth. Here we show that in NB cells, BDNF stimulates the synthesis of NPY and induces expression of another one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R positively correlated with the expression of BDNF and TrkB. Functionally, BDNF triggered Y5R internalization in NB cells, whereas Y5R antagonist inhibited BDNF-induced p44/42 mitogen-activated protein kinase activation and its pro-survival activity. These observations suggested TrkB-Y5R transactivation that resulted in cross-talk between their signaling pathways. Additionally, NPY and Y5R were upregulated in a BDNF-independent manner in NB cells under pro-apoptotic conditions, such as serum deprivation and chemotherapy, as well as in cell lines and tissues derived from posttreatment NB tumors. Blocking Y5R in chemoresistant NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis and inhibited their growth in vivo by augmenting cell death. In summary, the NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via its interactions with TrkB receptor and exerts an additional BDNF-independent anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, the NPY/Y5R pathway may become a novel therapeutic target for patients with refractory NB, thus far an incurable form of this disease.

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Acknowledgements

Human NB samples at diagnosis were provided by the Children’s Oncology Group. We thank Dr Garret Brodeur for providing SY5Y/TrkB transfectants. This work was supported by the National Institutes of Health grants: UL1TR000101 (previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS), through the Clinical and Translational Science Awards Program (CTSA), 1R01CA123211 and 1R03CA178809 to JK, as well as funding from Children’s Cancer Foundation (Baltimore, MD, USA) to JK, and Georgetown Undergraduate Research Opportunities Program to MH and DC. Experiments were performed with use of the Lombardi Comprehensive Cancer Center Shared Resources (Histopathology and Tissue, Biostatistics and Bioinformatics, Microscopy and Imaging, Animal Model and Tissue Culture) partially supported by the NIH/NCI grant P30-CA051008. We thank Dr Aykut Üren, Dr Ruijun Han and Dr Kristi Graves for their critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington,, DC, USA

    M Czarnecka, E Trinh, A Kuan-Celarier, S Galli, N Talisman, J Tsuei, C Yang, L Everhart, I Maheswaran & J Kitlinska

  2. McGovern Institute, Massachusetts Institute of Technology, Boston, MA, USA

    C Lu

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

    S-H Hong

  4. Department of Nursing, School of Nursing and Health Studies, Georgetown University, Washington,, DC, USA

    J U Tilan

  5. Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington,, DC, USA

    J U Tilan, S Martin, M Horton & D Christian

  6. Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, Poland,

    E Izycka-Swieszewska

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  1. M Czarnecka
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Czarnecka, M., Trinh, E., Lu, C. et al. Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance. Oncogene 34, 3131–3143 (2015). https://doi.org/10.1038/onc.2014.253

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