IFN-gammaupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma.

Academic Article


  • Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmodulin antagonists tamoxifen and trifluoperazine and are tumorigenic in nude mice (Pan et al., Am J Pathol 1999;155:193-203). Here, we show that IFN-gamma enhances apoptosis in both Fas-high and Fas-low cells. IFN-gamma upregulates many apoptosis-related molecules, including Fas, caspase-3, caspase-4, caspase-7, caspase-8 and Bak, in both cell lines. Pretreatment with IFN-gamma facilitated Fas-mediated caspase cleavage, cytochrome c release and Bax translocation. The ability of IFN-gamma to inhibit tumorigenesis of Fas-low cells was demonstrated in nude mice. Intratumoral injection of IFN-gamma decreased tumor volumes by 78%. These findings indicate that IFN-gamma modulates the apoptotic pathway by upregulating apoptosis-related genes. This renders tumorigenic Fas-low cholangiocarcinoma cells nontumorigenic and sensitive to Fas apoptosis, thus representing a possible therapeutic modality.
  • Published In


  • Apoptosis, Apoptosis Regulatory Proteins, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Biological Transport, Carcinogenicity Tests, Caspases, Cholangiocarcinoma, Cytochrome c Group, Genetic Variation, Humans, Interferon-gamma, Membrane Glycoproteins, Membrane Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Up-Regulation, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, fas Receptor
  • Digital Object Identifier (doi)

    Pubmed Id

  • 22122543
  • Author List

  • Ahn E-Y; Pan G; Vickers SM; McDonald JM
  • Start Page

  • 445
  • End Page

  • 451
  • Volume

  • 100
  • Issue

  • 4