title: Interleukin-6 drives melanoma cell motility through p38α-MAPK-dependent up-regulation of WNT5A expression.
abstract: Extensive research has demonstrated a tumor-promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up-regulated in melanoma. A potential regulator of WNT5A expression is the pro-inflammatory cytokine Interleukin (IL)-6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL-6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A-antagonistic peptide Box5 could inhibit IL-6-induced melanoma cell migration and invasion. Furthermore, IL-6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose-dependent manner. To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I-201 failed to inhibit IL-6-induced WNT5A up-regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL-6-induced activation of p38-MAPK in HTB63 and A375 cells. The p38-MAPK inhibitor SB203580 abolished the IL-6-induced WNT5A up-regulation and blocked IL-6-induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38α-MAPK isoform was activated by IL-6, and subsequent siRNA silencing of p38α-MAPK abolished the IL-6-induced up-regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro-metastatic agents IL-6 and WNT5A explaining how IL-6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.
authors: Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors: Rickard
authors: R
authors: Linnskog
authors: Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors: Gunilla
authors: G
authors: Jönsson
authors: Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors: Lena
authors: L
authors: Axelsson
authors: Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors: Chandra P
authors: CP
authors: Prasad
authors: Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden. Electronic address: tommy.andersson@med.lu.se.
authors: Tommy
authors: T
authors: Andersson
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071818:Wnt-5a Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D015850:Interleukin-6; C545555:N-butyloxycarbonyl-methionyl-aspartyl-glycyl-cysteinyl-glutamyl-leucine; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Cell motility; Interleukin-6; Melanoma; STAT3; WNT5A; p38 MAPK