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

Int J Cancer. 2002 Aug 1;100(4):445-51. doi: 10.1002/ijc.10516.

Abstract

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.

Publication types

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

MeSH terms

  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Bile Duct Neoplasms / pathology*
  • Bile Ducts, Intrahepatic / pathology*
  • Biological Transport
  • Carcinogenicity Tests
  • Caspases / metabolism
  • Cholangiocarcinoma / pathology*
  • Cytochrome c Group / metabolism
  • Genetic Variation
  • Humans
  • Interferon-gamma / pharmacology*
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • fas Receptor / drug effects
  • fas Receptor / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • BAK1 protein, human
  • BAX protein, human
  • Cytochrome c Group
  • Membrane Glycoproteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • fas Receptor
  • Interferon-gamma
  • Caspases