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


CONCLUSIONS
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.
Konturek
Peter C
PC
First Department of Medicine, University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany. pkonturek@web.de
Burnat
Grzegorz
G
Rau
Tilman
T
Hahn
Eckhart G
EG
Konturek
Stanislaw
S
D000230:Adenocarcinoma / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001471:Barrett Esophagus / Q000378:metabolism*; D045744:Cell Line, Tumor; D003470:Culture Media; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003840:Deoxycholic Acid; D004848:Epithelium / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism*; D054439:Ghrelin / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053583:Interleukin-1beta / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; D003470:Culture Media; D054439:Ghrelin; D053583:Interleukin-1beta; D054419:Receptors, Adiponectin; D054440:Receptors, Ghrelin; D014409:Tumor Necrosis Factor-alpha; D003840:Deoxycholic Acid; D051546:Cyclooxygenase 2