title: The JAK/STAT pathway is not sufficient to sustain the antiproliferative response in an interferon-resistant human melanoma cell line.
abstract: The mechanism of resistance of malignant melanoma to treatment with interferon-alpha is unknown, and currently there is no reliable method of predicting response. Signalling via the JAK/STAT pathway is known to mediate many interferon-regulated events and has been implicated in mediating the antiproliferative response. The objective of this study was to determine whether defects in JAK/STAT signalling may be responsible for interferon resistance. The in vitro response to interferon was determined in a panel of established melanoma cell lines, and the components and functioning of the JAK/STAT pathway were examined in sensitive and resistant cell lines. Two melanoma cell lines, characterized as sensitive (MM418) and resistant (MeWo) to the antiproliferative effect of interferon, were both shown by Western blotting to possess all the protein components of the JAK/STAT pathway, and were shown to be capable of producing functional transcription factors using an electrophoretic mobility shift assay and a ribonuclease protection assay of known interferon-induced genes. In addition, both cell lines had intact antiviral and HLA upregulation responses. These data suggest that there is no defect in the JAK/STAT pathway per se in the MeWo cell line, and that the substantial resistance to interferon must be mediated through components either downstream or additional to this signalling pathway. Others have shown JAK/STAT defects to be responsible for interferon resistance in some melanoma cell lines. However, our results highlight the likely heterogeneity in the mechanisms leading to interferon resistance both in cell lines and tumours, and suggest that a clinical assay based on analysis of components of the JAK/STAT pathway may have only limited use as a predictor of interferon response.
authors.affiliation: Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, UK. d.p.jackson@cancermed.leeds.ac.uk
authors.forename: David P
authors.initials: DP
authors.lastname: Jackson
authors.forename: Diane
authors.initials: D
authors.lastname: Watling
authors.forename: Neil C
authors.initials: NC
authors.lastname: Rogers
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.forename: Ian M
authors.initials: IM
authors.lastname: Kerr
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Selby
authors.forename: Poulam M
authors.initials: PM
authors.lastname: Patel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D007372:Interferons; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3