Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells

Br J Surg. 2007 Mar;94(3):346-54. doi: 10.1002/bjs.5530.

Abstract

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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Apoptosis
  • Cell Proliferation
  • Colonic Neoplasms / etiology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Leptin / metabolism*
  • Mitogen-Activated Protein Kinases / physiology
  • Obesity / complications*
  • Phosphatidylinositol 3-Kinases / physiology
  • Risk Factors
  • Tumor Cells, Cultured

Substances

  • Leptin
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases