Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells

Gastroenterology. 2005 Jun;128(7):2054-65. doi: 10.1053/j.gastro.2005.03.010.

Abstract

Background & aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / pathology*
  • Drug Resistance
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Interleukin-6 / pharmacology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Membrane Glycoproteins / pharmacology*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / biosynthesis*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation
  • fas Receptor

Substances

  • Apoptosis Regulatory Proteins
  • Interleukin-6
  • Membrane Glycoproteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt