Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion

Sharon DeMorrow, Paolo Onori, Julie Venter, Pietro Invernizzi, Gabriel Frampton, Mellanie White, Antonio Franchitto, Shelley Kopriva, Francesca Bernuzzi, Heather Francis, Monique Coufal, Shannon Glaser, Giammarco Fava, Fanyin Meng, Domenico Alvaro, Guido Carpino, Eugenio Gaudio, Gianfranco Alpini

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular D-myo-inositol 1,4,5- trisphosphate and PKCα activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume300
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Keywords

  • Cholangiocyte
  • Microenvironment
  • Migration
  • Protein kinase C

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

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  • Cite this

    DeMorrow, S., Onori, P., Venter, J., Invernizzi, P., Frampton, G., White, M., Franchitto, A., Kopriva, S., Bernuzzi, F., Francis, H., Coufal, M., Glaser, S., Fava, G., Meng, F., Alvaro, D., Carpino, G., Gaudio, E., & Alpini, G. (2011). Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion. American Journal of Physiology - Cell Physiology, 300(5). https://doi.org/10.1152/ajpcell.00358.2010