title: Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells.
abstract: Obesity increases the risk of colon cancer. Hyperleptinemia is characteristic of obesity and leptin has been reported to be a colonic growth factor. We have examined the involvement of the cyclo-oxygenase (COX) pathways in the proliferation and anti-apoptotic effects of leptin. Leptin stimulated proliferation in HT-29 colon cancer cells: this was unaffected by inhibition of COX-1, COX-2, protein kinase C, or the epidermal growth factor receptor. Leptin did not increase COX-2 mRNA or COX-derived prostaglandin E2 production. Celecoxib induced apoptosis in a COX-independent manner. Leptin reduced both serum starvation- and celecoxib-induced apoptosis. Inhibition of ERK, p38 MAP kinase, and nuclear factor (NF)-kappaB abolished the growth-promoting and anti-apoptotic effects of leptin. Treatment of HT-29 cells with leptin stimulated phosphorylation of ERK and p38 MAP kinase and nuclear translocation of active NF-kappaB. We conclude that leptin stimulates colon cancer proliferation via COX-independent pathways and reduces celecoxib-induced apoptosis via ERK, p38 MAP kinase, and NF-kappaB pathways.
authors.affiliation: Gastroenterology Research Unit, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK.
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 / Q000187:drug effects*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis; D016328:NF-kappa B / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D020738:Leptin; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020929:Mitogen-Activated Protein Kinase Kinases; D000068579:Celecoxib