Gastrin stimulates receptor-mediated proliferation of human esophageal adenocarcinoma cells.
The prevalence of esophageal adenocarcinoma in the setting of Barrett's metaplasia continues to increase in Western nations at a rate greater than any other cancer. The trophic properties of gastrin have been documented in gastric, pancreatic and colon cancer cell lines, suggesting a potential role for this regulatory peptide in the growth of these malignancies. The aims of these studies were to identify and characterize the presence of functional cholecystokinin type-2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of cholecystokinin type-2 receptor transcripts in human esophageal adenocarcinoma cell lines. Competitive binding assays revealed specific binding of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by laser scanning confocal microscopy through internalization of rhodamine green labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent increase in proliferation of SEG-1 cells when compared to controls. This effect was abolished by co-incubation with L365,260, a CCK-2-specific receptor antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated protein kinases was demonstrated by Western blot analysis. In conclusion, the studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2 (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation in SEG-1 cells.
Moore
T Carlton
TC
Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 650 Albany Street, EBRC Fifth Floor, MA 02118, USA.
Jepeal
Lisa I
LI
Boylan
Michael O
MO
Singh
Satish K
SK
Boyd
Nick
N
Beer
David G
DG
Chang
Albert J
AJ
Wolfe
M Michael
MM
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001667:Binding, Competitive; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005755:Gastrins / Q000494:pharmacology*; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D001570:Benzodiazepinones; D005755:Gastrins; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; C058121:L 365260