Jackson David P, Watling Diane, Rogers Neil C, Banks Rosamonde E, Kerr Ian M, Selby Peter J, Patel Poulam M
Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, UK.
Melanoma Res. 2003 Jun;13(3):219-29. doi: 10.1097/00008390-200306000-00001.
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.
恶性黑色素瘤对α-干扰素治疗产生耐药性的机制尚不清楚，目前尚无可靠的方法来预测疗效。已知通过JAK/STAT途径发出的信号介导许多受干扰素调节的事件，并与介导抗增殖反应有关。本研究的目的是确定JAK/STAT信号通路的缺陷是否可能是导致干扰素耐药的原因。在一组已建立的黑色素瘤细胞系中测定了对干扰素的体外反应，并在敏感和耐药细胞系中检测了JAK/STAT途径的组成成分和功能。两种黑色素瘤细胞系，一种对干扰素的抗增殖作用敏感（MM418），另一种耐药（MeWo），蛋白质印迹法显示二者均具有JAK/STAT途径的所有蛋白质成分，并且通过电泳迁移率变动分析和对已知干扰素诱导基因的核糖核酸酶保护分析表明它们能够产生功能性转录因子。此外，两种细胞系均具有完整的抗病毒和HLA上调反应。这些数据表明，MeWo细胞系本身的JAK/STAT途径没有缺陷，对干扰素的显著耐药性必定是通过该信号通路下游或其他的成分介导的。其他人已经表明JAK/STAT缺陷是某些黑色素瘤细胞系中干扰素耐药的原因。然而，我们的结果突出了在细胞系和肿瘤中导致干扰素耐药的机制可能存在异质性，并表明基于JAK/STAT途径成分分析的临床检测作为干扰素反应预测指标的作用可能有限。
