Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells.
Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melanoma B16-F10.9 by addition of recombinant soluble IL-6 receptor alpha-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to specific IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and differentiation of the metastatic melanoma cells. Previously observed antimetastatic effects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and differentiation elicited by sIL-6R present in biological fluids.
Oh
J W
JW
Department of Molecular Genetics, Weizmann Institute of Science, Rehovoth, Israel.
Katz
A
A
Harroch
S
S
Eisenbach
L
L
Revel
M
M
Chebath
J
J
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6 / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D012995:Solubility; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators