Obesity is associated with increased levels of leptin. The mitogenic actions of leptin have been identified in various cell types. Because obesity may be a risk factor for colonic cancer, the proliferative and antiapoptotic effects of leptin on colonic cancer cells and the role of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K) signalling were investigated.Methods
Three human colonic cancer cell lines (T84, HT29/Cl.19A and Caco-2) were treated with leptin. Cell proliferation was measured using the XTT® colorimetric assay and apoptosis by a cell death enzyme-linked immunosorbent assay. Inhibitors of MAPK and PI3-K were used to evaluate the role of these signalling pathways. Phosphorylation of the downstream components extracellular signal-regulated kinase (ERK) 1/2 and Akt was detected by western blotting.Results
Leptin increased cell number in all cell lines in a dose-dependent manner and reduced the number of apoptotic cells in a cell line-dependent manner. Leptin also caused ERK1/2 and Akt phosphorylation. Pretreatment with inhibitors of MAPK and PI3-K inhibited these responses, attenuated the mitogenic action of leptin and abolished its antiapoptotic effects.Conclusion
Chronic increases in leptin concentration may enhance the growth of colonic cancers via MAPK and PI3-K pathways. These effects of leptin could provide a link between obesity and colonic cancer, and may represent a target for anticancer drug development.