Wellbrock Claudia, Weisser Christin, Hassel Jessica C, Fischer Petra, Becker Jürgen, Vetter Claudia S, Behrmann Iris, Kortylewski Marcin, Heinrich Peter C, Schartl Manfred
Department of Physiological Chemistry I, Biocenter, Theodor-Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Curr Biol. 2005 Sep 20;15(18):1629-39. doi: 10.1016/j.cub.2005.08.036.
Malignant melanoma is a highly aggressive neoplastic disease whose incidence is increasing rapidly. In recent years, the use of interferon alpha (IFNalpha) has become the most established adjuvant immunotherapy for melanoma of advanced stage. IFNalpha is a potent inhibitor of melanoma cell proliferation, and the signal transducer and activator of transcription STAT1 is crucial for its antiproliferative action. Although advanced melanomas clinically resistant to IFNalpha are frequently characterized by inefficient STAT1 signaling, the mechanisms underlying advanced-stage interferon resistance are poorly understood.
Here, we demonstrate that IFNalpha activates STAT5 in melanoma cells and that in IFNalpha-resistant cells STAT5 is overexpressed. Significantly, the knockdown of STAT5 in interferon-resistant melanoma cells restored the growth-inhibitory response to IFNalpha. When STAT5 was overexpressed in IFNalpha-sensitive cells, it counteracted interferon-induced growth inhibition. The overexpressed STAT5 diminished IFNalpha-triggered STAT1 activation, most evidently through upregulation of the inhibitor of cytokine-signaling CIS.
Our data demonstrate that overexpression and activation of STAT5 enable melanoma cells to overcome cytokine-mediated antiproliferative signaling. Thus, overexpression of STAT5 can counteract IFNalpha signaling in melanoma cells, and this finally can result in cytokine-resistant and progressively growing tumor cells. These findings have significant implications for the clinical failure of IFNalpha therapy of advanced melanoma because they demonstrate that IFNalpha induces the activation of STAT5 in melanoma cells, and in STAT5-overexpressing cells, this contributes to IFNalpha resistance.
恶性黑色素瘤是一种侵袭性很强的肿瘤疾病，其发病率正在迅速上升。近年来，α干扰素（IFNα）的使用已成为晚期黑色素瘤最成熟的辅助免疫疗法。IFNα是黑色素瘤细胞增殖的有效抑制剂，信号转导和转录激活因子STAT1对其抗增殖作用至关重要。尽管临床上对IFNα耐药的晚期黑色素瘤通常表现为STAT1信号传导效率低下，但晚期干扰素耐药的潜在机制仍知之甚少。
在这里，我们证明IFNα在黑色素瘤细胞中激活STAT5，并且在IFNα耐药细胞中STAT5过表达。重要的是，在干扰素耐药的黑色素瘤细胞中敲低STAT5可恢复对IFNα的生长抑制反应。当STAT5在IFNα敏感细胞中过表达时，它会抵消干扰素诱导的生长抑制。过表达的STAT5减少了IFNα触发的STAT1激活，最明显的是通过上调细胞因子信号抑制因子CIS。
我们的数据表明，STAT5的过表达和激活使黑色素瘤细胞能够克服细胞因子介导的抗增殖信号。因此，STAT5的过表达可以抵消黑色素瘤细胞中的IFNα信号，这最终可能导致细胞因子耐药和肿瘤细胞逐渐生长。这些发现对晚期黑色素瘤IFNα治疗的临床失败具有重要意义，因为它们表明IFNα在黑色素瘤细胞中诱导STAT5的激活，而在STAT5过表达的细胞中，这会导致IFNα耐药。
