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 α (IFNα) has become the most established adjuvant immunotherapy for melanoma of advanced stage. IFNα 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 IFNα are frequently characterized by inefficient STAT1 signaling, the mechanisms underlying advanced-stage interferon resistance are poorly understood. Results: Here, we demonstrate that IFNα activates STAT5 in melanoma cells and that in IFNα-resistant cells STAT5 is overexpressed. Significantly, the knockdown of STAT5 in interferon-resistant melanoma cells restored the growth-inhibitory response to IFNα. When STAT5 was overexpressed in IFNα-sensitive cells, it counteracted interferon-induced growth inhibition. The overexpressed STAT5 diminished IFNα-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 antiproliferative signaling. Thus, overexpression of STAT5 can counteract IFNα 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 IFNα therapy of advanced melanoma because they demonstrate that IFNα induces the activation of STAT5 in melanoma cells, and in STAT5-overexpressing cells, this contributes to IFNα resistance. ©2005 Elsevier Ltd. All rights reserved.