Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways.
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.
Ogunwobi
Olorunseun Olatunji
OO
Gastroenterology Research Unit School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.
Beales
Ian L P
IL
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
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