Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells.
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.
Ogunwobi
Olorunseun Olatunji
OO
Gastroenterology Research Unit, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK.
Beales
Ian L P
IL
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
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