title: Molecular mechanisms of constitutive and inducible NF-kappaB activation in oesophageal adenocarcinoma.
abstract: BACKGROUND
  Nuclear factor-kappaB (NF-κB) regulates the expression of a large number of genes involved in the immune and inflammatory response. NF-κB 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-κB activation in oesophageal adenocarcinoma.
  
  
  METHODS
  Fresh biopsy specimens were obtained from 20 patients with oesophageal adenocarcinoma. The activation of NF-κB 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-α/β) and extracellular signal-regulated kinase 1/2 (ERK1/2) was examined by Western blotting. High content analysis was used to quantify NF-κB translocation in oesophageal cells.
  
  
  RESULTS
  Oesophageal tumour tissues had higher levels of NF-κB. Increased levels of phosphorylated AKT and IKK-α/β 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-κB activation and phosphorylation of AKT, IKK-α/β 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-κB activation. The proteasome inhibitor MG-132 and the antioxidants vitamin C and pyrrolidine dithiocarbamate (PDTC) also inhibited NF-κB activation.
  
  
  CONCLUSIONS
  Our data demonstrate a major role for PI3K/AKT-IKK-α/β-ERK1/2 signalling pathway in NF-κB activation in oesophageal adenocarcinoma. These results suggest that NF-κB may be a prognostic marker for oesophageal adenocarcinoma, and modulating of NF-κB may uncover new therapeutic strategies.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, Egypt; Department of Surgery, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Mohamed M M
authors.initials: MMM
authors.lastname: Abdel-Latif
authors.affiliation: Department of Clinical Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.affiliation: Department of Surgery, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland. Electronic address: reynoljv@tcd.ie.
authors.forename: John V
authors.initials: JV
authors.lastname: Reynolds
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D003840:Deoxycholic Acid / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D003840:Deoxycholic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Acid; DCA; HCA; NF-κB; Oesophageal adenocarcinoma