title: Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion.
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.
authors.affiliation: Texas A&M Health Science Center College of Medicine, 702 SW H. K. Dodgen Loop, Temple, TX, 76504. galpini@tamu.edu or galpini@medicine.tamhsc.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.forename: Mellanie
authors.initials: M
authors.lastname: White
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Shelley
authors.initials: S
authors.lastname: Kopriva
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Monique
authors.initials: M
authors.lastname: Coufal
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Giammarco
authors.initials: G
authors.lastname: Fava
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009478:Neuropeptide Y / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors
chemical_list: D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C