title: Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells.
abstract: OBJECTIVE
  Cholangiocarcinomas often arise within a background of chronic inflammation suggesting that inflammation imparts survival signals to this cancer. Previous studies have also shown that the inflammatory cytokine interleukin (interleukin [IL]-6) contributes to survival signals in an autocrine fashion and that myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the B-cell leukemia-2 family, is an important participant in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in this neoplasm. The present study evaluated the possibility that IL-6 signaling contributes to Mcl-1 up-regulation in cholangiocarcinoma.
  
  
  METHODS
  Protein kinase B (Akt) and Mcl-1 expression in human tissue was assessed by immunohistochemistry. The relationship between IL-6 signaling, Akt activity, and Mcl-1 expression was examined in cell lines.
  
  
  RESULTS
  Immunohistochemistry showed that the serine/threonine kinase Akt and Mcl-1 are strongly expressed in the preneoplastic bile duct inflammatory disease primary sclerosing cholangitis and in human cholangiocarcinoma specimens. Immunoblotting showed that Akt is expressed and constitutively phosphorylated in 3 human cholangiocarcinoma lines. Further analysis showed that treatment with anti-IL-6-neutralizing antiserum led to reduced Akt phosphorylation, diminished Mcl-1 expression, and enhanced TRAIL sensitivity. Likewise, the Akt inhibitor A443654.3 led to diminished signaling through the Akt pathway, decreased Mcl-1 expression, and enhanced TRAIL-mediated apoptosis.
  
  
  CONCLUSIONS
  These findings not only show that an autocrine IL-6/Akt signaling pathway enhances Mcl-1 expression in cholangiocarcinoma but also suggest a strategy for overcoming the resulting apoptosis resistance.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Werneburg
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D018281:Cholangiocarcinoma / Q000235:genetics / Q000473:pathology*; D004351:Drug Resistance; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D019014:fas Receptor
chemical_list: D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt