Submitted on January 10, 2008
Accepted on August 16, 2008
Gastrin increases mcl-1 expression in type 1 gastric carcinoid tumors and a gastric epithelial cell line which expresses the CCK-2 receptor
David Mark Pritchard1*, David Berry1, Sabine M.C. Przemeck1, Fiona Campbell2, Steven W Edwards3, and Andrea Varro4
1 Gastroenterology, University of Liverpool, Liverpool, United Kingdom
2 Pathology, Royal Liverpoool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom
3 Biological Sciences, University of Liverpool, Liverpool, United Kingdom
4 Physiology, University of Liverpool, Liverpool, United Kingdom
* To whom correspondence should be addressed. E-mail: dmpritch{at}liv.ac.uk.
Elevated serum concentrations of the hormone gastrin are associated with the development of gastric carcinoid tumors, but the mechanisms of tumor development are not fully understood. We hypothesized that the anti-apoptotic effects of gastrin may be implicated and have therefore investigated the role of anti-apoptotic members of the bcl-2 family of proteins. AGS-GR human gastric carcinoma cells stably transfected with the CCK-2 receptor were used to assess changes in the expression of bcl-2 family members following gastrin treatment and the function of mcl-1 during apoptosis was investigated using siRNA. Treatment of AGS-GR cells with 10nM gastrin for 6h caused maximally increased mcl-1 protein abundance. Gastrin-induced mcl-1 expression was inhibited by the transcription inhibitor actinomycin D and by the protein synthesis inhibitor cycloheximide. Downstream signalling of mcl-1 expression occurred via the CCK-2 receptor, protein kinase C and MAP kinase pathways, but not via PI 3-kinase. Transfection with mcl-1 siRNA significantly suppressed mcl-1 protein expression and abolished the anti-apoptotic effects of gastrin upon serum starvation-induced apoptosis. Mcl-1 protein expression was also specifically increased in the type I enterochromaffin like (ECL)-cell carcinoid tumors of ten patients with autoimmune atrophic gastritis and hypergastrinemia. Gastrin therefore signals via the CCK-2 receptor, protein kinase C and MAP kinase to induce expression of anti-apoptotic mcl-1 in AGS-GR cells and mcl-1 expression is also increased in human hypergastrinemia-associated type I gastric carcinoid tumors. Gastrin-induced mcl-1 expression may therefore be an important mechanism contributing towards type I gastric carcinoid development.
