Glycine-extended gastrin stimulates proliferation via JAK2- and Akt-dependent NF-kappaB activation in Barrett's oesophageal adenocarcinoma cells

Abstract

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.