An antiapoptotic role for gastrin and the gastrin/CCK-2 receptor in Barrett's esophagus.
Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.
Harris
Joseph C
JC
Academic Unit of Cancer Studies, West Block, Queen's Medical Center, University Hospital, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
Clarke
Philip A
PA
Awan
Altaf
A
Jankowski
Janusz
J
Watson
Susan A
SA
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D001569:Benzodiazepines / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005755:Gastrins / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D005755:Gastrins; D006727:Hormone Antagonists; D011518:Proto-Oncogene Proteins; D043887:Receptor, Cholecystokinin B; D001569:Benzodiazepines; C087260:YM 022; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt