STAT5 contributes to interferon resistance of melanoma cells

Background: Malignant melanoma is a highly aggressive neoplastic disease whose incidence is increasing rapidly. In recent years, the use of interferon alpha (IFN alpha) has become the most established adjuvant immunotherapy for melanoma of advanced stage. IFN alpha 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 IFN alpha are frequently characterized by inefficient STAT1 signaling, the mechanisms underlying advanced-stage interferon resistance are poorly understood. Results: Here, we demonstrate that IFN alpha activates STAT5 in melanoma cells and that in IFN alpha-resistant cells STAT5 is overexpressed. Significantly, the knockdown of STAT5 in interferon-resistant melanoma cells restored the growth-inhibitory response to IFN alpha. When STAT5 was overexpressed in IFN alpha-sensitive cells, it counteracted interferon-induced growth inhibition. The overexpressed STAT5 diminished IFN alpha-triggered STAT1 activation, most evidently through upregulation of the inhibitor of cytokine-signaling CIS. Conclusions: Our data demonstrate that overexpression and activation of STAT5 enable melanoma cells to overcome cytokine-mediated anti proliferative signaling. Thus, overexpression of STAT5 can counteract IFN alpha 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 IFN alpha therapy of advanced melanoma because they demonstrate that IFN alpha induces the activation of STAT5 in melanoma cells, and in STAT5-overexpressing cells, this contributes to IFN alpha resistance.