Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

Abstract

The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the evolution of an IFN-resistant state in vitro using melanoma cell lines. We found that the cells became less sensitive to antiproliferative effect of IFN-g after prolonged cultivation enabling us to isolate sensitive and resistant subclones of the parental line. We investigated transcription of signal transducer and activator of transcription (STAT) 1 -6 and suppressor of cytokine signalling (SOCS) 1 -3 genes, and phosphorylation of STAT 1 protein. The resistant subline (termed WM 1158R) differed from the sensitive subline (WM 1158S) by a constitutive expression of SOCS 3, lack or weak SOCS 1 -3 activation following IFN-g, and short duration of cytokine activatory signal. Similar correlations were observed in additional melanoma lines differing in IFN sensitivities. At the protein level, IFN-g induced strong and prolonged STAT 1 activation at serine 727 (S727) in WM 1158R while in WM 1158S cells phosphorylation of this amino acid was much less pronounced. On the other hand, phosphorylation of tyrosine 701 (Y701) was stimulated regardless of the sensitivity phenotype. In conclusion, constitutive expression of SOCS 3 is correlated with attenuation of its induction following IFN treatment. These results suggest that progression of melanoma cells from IFN sensitivity to IFN insensitivity associates with changes in SOCS expression.

Reduced inducibility of SOCS3 by interferon gamma associates with higher resistance of human breast cancer lines as compared to normal mammary epithelial cells

“…The data showed apparent similarities with other studies of molecular basis of cytokine sensitivity [24,25,26] allowing some generalization of our findings. First, cells that do not activate SOCS3 are usually resistant to IFN-gamma.…”

“…This is a likely reason for weak or negligible SOCS3 induction in most "non-responsive" breast cancer lines (Table 2). However, the duration of SOCS3 activation in MDA-MB-468 was similar to that of normal cells [35] but significantly shorter than in melanoma [25,26]. Perhaps, the SOCS3 half-life could differ among different cell types.…”

“…In melanoma cells high basal levels of SOCS3 were negatively correlated with the induction by IFN-gamma [25] and interleukin 10 [26]. Relatively high (3-fold over the average) basal SOCS3 levels could be a possible reason for SOCS3 induction failure in the CAMA-1 line.…”

“…It has been suggested that SOCS1 and SOCS3 are critical inhibitors of IFN-gamma signaling doi:10.4149/neo_2009_05_379 [5,23]. In support, the SOCS3 induction seems to be needed for antiproliferative effect of various cytokines including interferons in leukemia [24] and melanoma cells [25,26]. On the other hand, these and other studies [27,28] indicated that constitutive SOCS3 expression might confer growth advantage and resistance to various cytokine stimuli.…”

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

“…Indeed, reports describing SOCS-3 hypermethylation and subsequent loss of expression in a variety of cancers support the idea that SOCS-3 may have a tumor-suppressing function (94)(95)(96)(97). In contrast, elevated SOCS-3 expression was reported in human breast cancer and melanoma tissues, as well as in a subset of classic Hodgkin's lymphoma cell lines and primary lymphoma cells (98)(99)(100)(101)(102)(103)(104). In several studies, SOCS-3 promoted cell growth and proliferation in a number of cancers (100,103,105), and elevated levels of SOCS-3 were reported to confer a growth advantage to a melanoma cell line (103).…”