Melanoma cells exhibit variable signal transducer and activator of transcription 1 phosphorylation and a reduced response to IFN-alpha compared with immune effector cells.

Autor:	Lesinski GB; Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA., Trefry J, Brasdovich M, Kondadasula SV, Sackey K, Zimmerer JM, Chaudhury AR, Yu L, Zhang X, Crespin TR, Walker MJ, Carson WE 3rd
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2007 Sep 01; Vol. 13 (17), pp. 5010-9.
DOI:	10.1158/1078-0432.CCR-06-3092
Abstrakt:	Purpose: IFN-alpha is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-alpha. Experimental Design: Tyr(701)-phosphorylated STAT1 (P-STAT1) was measured by flow cytometry in IFN-alpha-stimulated human melanoma cell lines, melanoma cells derived from patient tumors, and peripheral blood mononuclear cells (PBMC). Expression of other Janus-activated kinase (Jak)-STAT intermediates (STAT1, STAT2, Jak1, tyrosine kinase 2, IFN-alpha receptor, STAT3, and STAT5) was evaluated by flow cytometry, immunoblot, or immunohistochemistry. Results: Significant variability in P-STAT1 was observed in human melanoma cell lines following IFN-alpha treatment (P < 0.05) and IFN-alpha-induced P-STAT1 correlated with the antiproliferative effects of IFN-alpha (P = 0.042). Reduced formation of P-STAT1 was not explained by loss of Jak-STAT proteins or enhanced STAT5 signaling as reported previously. Basal levels of P-STAT3 were inversely correlated with IFN-alpha-induced P-STAT1 in cell lines (P = 0.013). IFN-alpha-induced formation of P-STAT1 was also variable in melanoma cells derived from patient tumors; however, no relationship between P-STAT3 and IFN-alpha-induced P-STAT1 was evident. Because IFN-alpha acts on both tumor and immune cells, we examined the ability of IFN-alpha to induce P-STAT1 in patient-derived melanoma cells and PBMCs. IFN-alpha induced significantly lower levels of P-STAT1 in melanoma cells compared with matched PBMCs (P = 0.046). Melanoma cells and human melanocytes required 10-fold higher IFN-alpha doses to exert P-STAT1 levels comparable with PBMCs. Conclusions: Melanoma cells are variable in their IFN-alpha responsiveness, and cells of the melanocytic lineage exhibit a lower capacity for IFN-alpha-induced Jak-STAT signaling compared with immune cells.
Databáze:	MEDLINE
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