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-1β and COX-2 expression in OE-19 cells incubated with TNFα. 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 μg/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 TNFα or bile acids in the normal or pulse acidified medium, and the expression of IL-1β 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 TNFα-induced COX-2 and IL-1β 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.
KeywordsAdiponectin Ghrelin Barrett’s cancerogenesis Adipo-R1 Adipo-R2 TNFα IL-1β
- 10.Otake S, Takeda H, Suzuki Y, Fukui T, Watanabe S, Ishihama K, Saito T, Togashi H, Nakamura T, Matsuzawa Y, Kawata S (2005) Association of visceral fat accumulation and plasma adiponectin with colorectal adenoma: evidence for participation of insulin resistance. Clin Cancer Res 11:3642–36462PubMedCrossRefGoogle Scholar
- 15.Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141:4255–4261PubMedCrossRefGoogle Scholar
- 18.Suematsu M, Katsuki A, Sumida Y, Gabazza EC, Murashima S, Matsumoto K, Kitagawa N, Akatsuka H, Hori Y, Nakatani K, Togashi K, Yano Y, Adachi Y (2005) Decreased circulating levels of active ghrelin are associated with increased oxidative stress in obese subjects. Eur J Endocrinol 153:403–407PubMedCrossRefGoogle Scholar