Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Abstract

Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this e ect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 e ectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory e ect of OSM and IL-6 in A375 cells. In addition, we have identi®ed the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.

STAT3-mediated differentiation and survival of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27Kip1

“…Previously, it was shown that interleukin-6 and oncostatin M-induced growth inhibition of A375 melanoma cells is dependent on STAT3 activation and correlates with increased transcript levels of the cdk inhibitor p27 Kip1 (Kortylewski et al, 1999). Here, we report that STAT3 is involved in G-CSF-mediated di erentiation and survival and regulates the expression of p27 Kip1 .…”

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

“…STAT3 is know to exert different biological effects in different tissues; for instance, STAT3 is required for growth arrest and differentiation of some leukemia and melanoma cells. 53,54 However, STAT3 is expected to promote changes consistent with transformation in all the cell types analyzed in these studies. Another, related explanation is that epigenetic differences among the cell types influence the spectrum of genes STAT3 can bind to and activate; such potential differences include DNA methylation and histone modifications at the promoters of STAT targets.…”

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

“…They are in line with previous reports that showed that activated STAT3 does not induce features of increased malignancy in certain melanoma cell lines. For example, STAT3 activation actually led to growth inhibition of A375 17 and WM35 melanoma cells. 18 Two other canonical IL-6-signaling pathways, PI3K/Akt and MAPK, 3,7,48 -51 have been characterized thus far.…”

“…[13][14][15][16] In the A375 cell line, this inhibition is mediated by IL-6-induced STAT activation. 17,18 Cells derived from advanced melanomas at metastatic stages often lose this anti-proliferative response to IL-6. 16,19,20 In fact, antisense oligonucleotides blocking IL-6 gene expression inhibited the growth of these cell lines, suggesting that IL-6 promotes advanced stage melanoma cell growth by an autocrine mechanism.…”