title: CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells.
abstract: OBJECTIVE
  As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells.
  
  
  METHODS
  In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA.
  
  
  RESULTS
  Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360.
  
  
  CONCLUSIONS
  Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy.
authors.affiliation: Department of Clinical Research, Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Koichi
authors.initials: K
authors.lastname: Seto
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.forename: Mineo
authors.initials: M
authors.lastname: Takei
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D001570:Benzodiazepinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D043887:Receptor, Cholecystokinin B; D042461:Vascular Endothelial Growth Factor A; C528831:Z-360; D003841:Deoxycytidine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine