title: Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways.
abstract: Glycine-extended gastrin (G-Gly) is an end product of processing of the progastrin precursor peptide that has a different spectrum of activity to amidated gastrin. G-Gly promotes cell proliferation in normal and malignant colonic epithelium but the mechanisms responsible are poorly understood. Prostaglandins produced by the cyclo-oxygenase (COX) enzymes have been implicated as downstream mediators of several growth factors, and COX inhibitors such as non-steroidal anti-inflammatory drugs inhibit the proliferation and invasiveness of colonic cancer and reduce the incidence of colon cancer. We have examined the mechanisms of the actions of G-Gly in HT-29 colon cancer cells. G-Gly induced a dose-dependent increase in cell proliferation that was insensitive to inhibition of either COX-1 or COX-2, but was abolished by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. G-Gly did not increase prostaglandin E2 production. Celecoxib induced apoptosis and reduced viable cell numbers in a COX-independent manner. G-Gly significantly reduced serum-starvation and celecoxib-induced apoptosis and this effect was also blocked by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. Stimulation of HT-29 cells with G-Gly led to a rapid increase in ERK and p38 MAP kinase phosphorylation and increased nuclear translocation of active NF-kappaB. Activation of NF-kappaB was independent of ERK and p38 MAP kinase. G-Gly stimulates proliferation and inhibits apoptosis in colon cancer cells via COX-independent and ERK-, p38 MAP kinase-, and NF-kappaB-dependant pathways. Locally and systemically produced G-Gly may be important in reducing the beneficial effects of chemopreventative agents in colon cancer.
authors.affiliation: Gastroenterology Research Unit School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Olorunseun Olatunji
authors.initials: OO
authors.lastname: Ogunwobi
authors.forename: Ian L P
authors.initials: IL
authors.lastname: Beales
mesh_terms: D017209:Apoptosis; D000068579:Celecoxib; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D005755:Gastrins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; C086854:glycine-extended gastrin 17; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D000068579:Celecoxib; D015232:Dinoprostone