Glycine-extended gastrin stimulates proliferation via JAK2- and Akt-dependent NF-kappaB activation in Barrett's oesophageal adenocarcinoma cells.
Glycine-extended gastrin (G-Gly) is a mitogen for several gastrointestinal tissues although the mechanisms responsible are ill-defined and it is unknown if G-Gly can influence signalling in Barrett's oesophagus. G-Gly stimulated proliferation in OE19 and OE33 cells in a dose-dependant manner. This was unaffected by a CCK2 receptor antagonist but abolished by COX-2 inhibitors. G-Gly induced proliferation, COX-2 mRNA abundance, and PGE2 secretion, were all abolished by inhibition of JAK2, PI3-kinase, Akt or NF-kappaB. G-Gly stimulated phosphorylation of JAK2 and increased PI3-kinase activity in JAK2 immunoprecipitates. G-Gly increased Akt phosphorylation and kinase activity and NF-kappaB reporter activity in a JAK2-, PI3-kinase- and Akt-sensitive manner. G-Gly increased COX-2 promoter transcription in an Akt and NF-kappaB-dependent manner and also reduced COX-2 mRNA degradation in an Akt-insensitive manner. We conclude that G-Gly induced signalling involves a JAK2/PI3-kinase/Akt/NF-kappaB sequence leading to COX-2 transcription. G-Gly also seems to stabilise COX-2 mRNA via a separate pathway.
Ogunwobi
Olorunseun O
OO
Biomedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom.
Beales
Ian L P
IL
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005755:Gastrins / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects; D043887:Receptor, Cholecystokinin B / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D005755:Gastrins; D016328:NF-kappa B; D043887:Receptor, Cholecystokinin B; C086854:glycine-extended gastrin 17; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D051058:Oncogene Protein v-akt; D015232:Dinoprostone