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

• Published in: The Journal of biological chemistry 1997-11, Vol.272 (45), p.28779-28785
• Main Authors: Wong, L H, Krauer, K G, Hatzinisiriou, I, Estcourt, M J, Hersey, P, Tam, N D, Edmondson, S, Devenish, R J, Ralph, S J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Cytokines - metabolism; DNA-Binding Proteins - analysis; DNA-Binding Proteins - genetics; Drug Resistance, Neoplasm; Humans; Interferon-alpha - pharmacology; Interferon-Stimulated Gene Factor 3; Interferon-Stimulated Gene Factor 3, gamma Subunit; Interferons - therapeutic use; Janus Kinase 1; Melanoma - chemistry; Melanoma - genetics; Melanoma - metabolism; Phosphorylation; Protein-Tyrosine Kinases - metabolism; Proteins - metabolism; Signal Transduction; STAT1 Transcription Factor; STAT2 Transcription Factor; Trans-Activators - analysis; Trans-Activators - genetics; Transcription Factors - analysis; Transcription Factors - genetics; Tumor Cells, Cultured; TYK2 Kinase; Tyrosine - metabolism; Ubiquitins - analogs & derivatives
• ISSN: 0021-9258

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.