Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma

J Biol Chem. 1997 Nov 7;272(45):28779-85. doi: 10.1074/jbc.272.45.28779.


The mechanism of IFN resistance was examined in three long-term cell lines, SK-MEL-28, SK-MEL-3, and MM96, exhibiting significant variation in responsiveness to the antiproliferative and antiviral effects of type I IFNs. The JAK-STAT components involved in IFN signal transduction were analyzed in detail. After exposure to IFN, activation of the IFN type I receptor-linked tyrosine kinases, JAK-1 and TYK-2, was detected at similar levels in both IFN-sensitive and IFN-resistant cell types, indicating that IFN resistance did not result from a deficiency in signaling at the level of receptor-associated kinase activation. However, analysis of ISGF3 transcription factor components, STAT1, STAT2, and p48-ISGF3gamma, revealed that their expression and activation correlated with cellular IFN responsiveness. The analysis was extended to also include IFN-sensitive primary melanocytes, three additional IFN-resistant melanoma cell lines, and seven cell cultures recently established from melanoma patient biopsies. It was consistently observed that the most marked difference in ISGF3 was a lack of STAT1 in the resistant versus the sensitive cells. Transfection of the IFN-resistant MM96 cell line to express increased levels of STAT1 protein partially restored IFN responsiveness in an antiviral assay. We conclude that a defect in the level of STAT1 and possibly all three ISGF3 components in IFN-resistant human melanoma cells may be a general phenomenon responsible for reduced cellular responsiveness of melanomas to IFNs.

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Cytokines / metabolism
  • DNA-Binding Proteins / analysis*
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm*
  • Humans
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha / pharmacology
  • Interferons / therapeutic use*
  • Janus Kinase 1
  • Melanoma / chemistry
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Signal Transduction
  • TYK2 Kinase
  • Trans-Activators / analysis*
  • Trans-Activators / genetics
  • Transcription Factors / analysis*
  • Transcription Factors / genetics
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • Ubiquitins* / analogs & derivatives*


  • Antineoplastic Agents
  • Cytokines
  • DNA-Binding Proteins
  • IRF9 protein, human
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Trans-Activators
  • Transcription Factors
  • Ubiquitins
  • Tyrosine
  • ISG15 protein, human
  • Interferons
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human