Effect of adiponectin and ghrelin on apoptosis of Barrett adenocarcinoma cell line

Dig Dis Sci. 2008 Mar;53(3):597-605. doi: 10.1007/s10620-007-9922-1. Epub 2007 Sep 1.

Abstract

Background: Obesity is an important risk factor for Barrett adenocarcinoma. However, the role of adiponectin (anti-inflammatory adipokine from adipose tissue) and ghrelin (orexigenic peptide gastric origin) on the progression of Barrett's carcinogenesis has not been investigated so far. The aim of the present study was: (1) to compare the expression of adiponectin and ghrelin receptors in Barrett's esophagus and in normal squamous epithelium; (2) to assess the effect of adiponectin and ghrelin on apoptosis in Barrett's adenocarcinoma cells in vitro; and (3) to investigate the effect of ghrelin on IL-1beta and COX-2 expression in OE-19 cells incubated with TNFalpha.

Methods: The expression of ghrelin and adiponectin receptors (GHS-R1a, Adipo-R1, Adipo R-2) in biopsies from Barrett's esophagus and in Barrett's adenocarcinoma cell line OE-19 was assessed by quantitative RT-PCR (qRT-PCR). The OE-19 cells were also incubated with adiponectin (5-10 microg/ml), and the apoptosis and proliferation were assessed by FACS and MTT assays. Additionally, effects of adiponectin on the mRNA and protein expression of proapoptotic Bax and antiapoptotic Bcl-2 were assessed by RT-PCR and Western blot, respectively. In two different in vitro models of esophagitis the OE-19 cells were incubated with ghrelin alone or in the presence of TNFalpha or bile acids in the normal or pulse acidified medium, and the expression of IL-1beta and COX-2 as markers for inflammation were assessed by FACS and qRT-PCR, respectively.

Results: Adiponectin caused a significant increase in apoptosis, and this affect was accompanied by increased Bax and decreased Bcl-2 expression. In contrast, ghrelin had no effect on apoptosis of OE-19 cells incubated in neutral or acidified medium with or without addition of deoxycholic acid. At the mRNA level, the expression of adiponectin receptors (Adipo-R1, Adipo-R2) was decreased, and the expression of ghrelin receptor (GHS-R1a) was increased in Barrett's mucosa. Ghrelin caused a decrease in TNFalpha-induced COX-2 and IL-1beta expression in OE-19 cells.

Conclusion: Adiponectin and ghrelin have an inhibitory effect on Barrett's carcinogenesis by two different mechanisms: (1) by an increase in apoptosis by adiponectin, and (2) by anti-inflammatory actions of ghrelin. The decrease in levels of these two peptides in obesity may explain the progression of Barrett's carcinoma in obese individuals.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adiponectin / metabolism
  • Apoptosis / physiology*
  • Barrett Esophagus / metabolism*
  • Cell Line, Tumor
  • Culture Media
  • Cyclooxygenase 2 / metabolism
  • Deoxycholic Acid
  • Epithelium / metabolism
  • Esophageal Neoplasms / metabolism*
  • Ghrelin / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Interleukin-1beta / metabolism
  • Receptors, Adiponectin / metabolism*
  • Receptors, Ghrelin / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adiponectin
  • Culture Media
  • Ghrelin
  • Interleukin-1beta
  • Receptors, Adiponectin
  • Receptors, Ghrelin
  • Tumor Necrosis Factor-alpha
  • Deoxycholic Acid
  • Cyclooxygenase 2