Abstract
Background: Nuclear factor-kappaB (NF-kappa B) regulates the expression of a large number of genes involved in the immune and inflammatory response. NF-kappa B is constitutively activated in oesophageal tumour tissues and induced in oesophageal cells by bile and acid. The aim of the present study was to define the mechanisms underlying NF-kappa B activation in oesophageal adenocarcinoma.
Patients and methods: Fresh biopsy specimens were obtained from 20 patients with oesophageal adenocarcinoma. The activation of NF-kappa B in oesophageal tumour specimens and oesophageal SKGT-4 cells was assessed by gel mobility shift and Western blotting. Phosphorylation of protein kinase B (AKT/PKB), Ikappa kinase-alpha/beta (IKK-alpha/beta) and extracellular signal-regulated kinase 1/2 (ERK1/2) was examined by Western blotting. High content analysis was used to quantify NF-kappa B translocation in oesophageal cells.
Results: Oesophageal tumour tissues had higher levels of NF-kappa B. Increased levels of phosphorylated AKT and IKK-alpha/beta and ERK1/2 were detected in tumour tissues compared with normal oesophageal mucosa. Exposure of SKGT-4 cells to deoxycholic acid (DCA) or acid resulted in NF-kappa B activation and phosphorylation of AKT, IKK-alpha/beta and ERK1/2. Specific inhibitors for phosphoinositide 3-kinase; PI3K (LY294002 and worhmannin) and ERK1/2 inhibitors (PD98059 and U0126) suppressed DCA- and acid-induced NF-kappa B activation. The proteasome inhibitor MG-132 and the antioxidants vitamin C and pyrrolidine dithiocarbamate (PDTC) also inhibited NF-kappa B activation.
Conclusions: Our data demonstrate a major role for PI3K/AKT-IKK-alpha/beta-ERK1/2 signalling pathway in NF-kappa B activation in oesophageal adenocarcinoma. These results suggest that NF-kappa B may be a prognostic marker for oesophageal adenocarcinoma, and modulating of NF-kappa B may uncover new therapeutic strategies. (C) 2015 Published by Elsevier Ltd.