Original Article
Interferon-γ-Mediated Growth Regulation of Melanoma Cells: Involvement of STAT1-Dependent and STAT1-Independent Signals

https://doi.org/10.1046/j.0022-202X.2004.22237.xGet rights and content
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Interferon-γ, a known inhibitor of tumor cell growth, has been used in several protocols for the treatment of melanoma. We have studied the molecular events underlying interferon-γ-induced G0/G1 arrest in four metastatic melanoma cell lines with different responsiveness to interferon-γ. The growth arrest did not result from enhanced expression of cyclin-dependent kinase inhibitors p21 and p27. Instead, it correlated with downregulation of cyclin E and cyclin A and inhibition of their associated kinase activities. We show that interferon-γ-induced growth inhibition could be abrogated by overexpression of dominant negative STAT1 (signal transducer and activator of transcription 1) in the melanoma cell line A375, suggesting that STAT1 plays a crucial part for the anti-proliferative effect. Erythropoietin stimulation of a chimeric receptor led to a concentration-dependent STAT1 activation and concomitant growth arrest when it contained the STAT recruitment motif Y440 of the interferon-γ receptor 1. In contrast, dose–response studies for interferon-γ revealed a discrepancy between levels of STAT1 activation and the extent of growth inhibition; whereas STAT1 was activated by low doses of interferon-γ (10 U per mL), growth inhibitory effects were only visible with 100-fold higher concentrations. Our results suggest the presence of additional signals emanating from the interferon-γ receptor, which may counteract the anti-proliferative function of STAT1.

Keywords

cell cycle
chimeric receptor
cytokine resistance
cytokines
signal transduction

Cited by (0)

1

Present address: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

2

Present address: Laboratoire de Biologie et Physiologie Intégrée, Fac. Sciences, Techo. & Com., Université du Luxembourg, 1511 Luxembourg, Luxembourg.