Neuropeptide y and its Y2 receptor: Potential targets in neuroblastoma therapy

C. Lu, L. Everhart, J. Tilan, L. Kuo, C. C J Sun, R. B. Munivenkatappa, A. C. Jönsson-Rylander, J. Sun, A. Kuan-Celarier, L. Li, K. Abe, Z. Zukowska, J. A. Toretsky, J. Kitlinska

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5630-5642
Number of pages13
JournalOncogene
Volume29
Issue number41
DOIs
StatePublished - Oct 14 2010
Externally publishedYes

Fingerprint

Neuropeptides
Neuroblastoma
Neuropeptide Y
Therapeutics
Neoplasms
Mitogen-Activated Protein Kinases
Heterografts
Small Interfering RNA
Endothelial Cells
Apoptosis
In Situ Nick-End Labeling
Conditioned Culture Medium
Growth
Neurotransmitter Agents
Fibrosis
Cell Proliferation
Pediatrics
Cell Line
Peptides
Proteins

Keywords

  • angiogenesis
  • neuroblastoma
  • neuropeptide Y

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lu, C., Everhart, L., Tilan, J., Kuo, L., Sun, C. C. J., Munivenkatappa, R. B., ... Kitlinska, J. (2010). Neuropeptide y and its Y2 receptor: Potential targets in neuroblastoma therapy. Oncogene, 29(41), 5630-5642. https://doi.org/10.1038/onc.2010.301

Neuropeptide y and its Y2 receptor : Potential targets in neuroblastoma therapy. / Lu, C.; Everhart, L.; Tilan, J.; Kuo, L.; Sun, C. C J; Munivenkatappa, R. B.; Jönsson-Rylander, A. C.; Sun, J.; Kuan-Celarier, A.; Li, L.; Abe, K.; Zukowska, Z.; Toretsky, J. A.; Kitlinska, J.

In: Oncogene, Vol. 29, No. 41, 14.10.2010, p. 5630-5642.

Research output: Contribution to journalArticle

Lu, C, Everhart, L, Tilan, J, Kuo, L, Sun, CCJ, Munivenkatappa, RB, Jönsson-Rylander, AC, Sun, J, Kuan-Celarier, A, Li, L, Abe, K, Zukowska, Z, Toretsky, JA & Kitlinska, J 2010, 'Neuropeptide y and its Y2 receptor: Potential targets in neuroblastoma therapy', Oncogene, vol. 29, no. 41, pp. 5630-5642. https://doi.org/10.1038/onc.2010.301
Lu C, Everhart L, Tilan J, Kuo L, Sun CCJ, Munivenkatappa RB et al. Neuropeptide y and its Y2 receptor: Potential targets in neuroblastoma therapy. Oncogene. 2010 Oct 14;29(41):5630-5642. https://doi.org/10.1038/onc.2010.301
Lu, C. ; Everhart, L. ; Tilan, J. ; Kuo, L. ; Sun, C. C J ; Munivenkatappa, R. B. ; Jönsson-Rylander, A. C. ; Sun, J. ; Kuan-Celarier, A. ; Li, L. ; Abe, K. ; Zukowska, Z. ; Toretsky, J. A. ; Kitlinska, J. / Neuropeptide y and its Y2 receptor : Potential targets in neuroblastoma therapy. In: Oncogene. 2010 ; Vol. 29, No. 41. pp. 5630-5642.
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