Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells.
BACKGROUND
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 (T(84), 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.


CONCLUSIONS
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.
Hoda
M R
MR
Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, San Diego, California, USA.
Keely
S J
SJ
Bertelsen
L S
LS
Junger
W G
WG
Dharmasena
D
D
Barrett
K E
KE
D000704:Analysis of Variance; D017209:Apoptosis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000209:etiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D020738:Leptin / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009765:Obesity / Q000150:complications*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D012307:Risk Factors; D014407:Tumor Cells, Cultured
D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases