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Interleukin-6 drives melanoma cell motility through p38α-MAPK-dependent up-regulation of WNT5A expression.

Linnskog, Rickard LU ; Jönsson, Gunilla LU ; Axelsson, Lena LU ; Prasad, Chandra LU and Andersson, Tommy LU (2014) In Molecular Oncology 8(8). p.1365-1378
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Oncology
volume
8
issue
8
pages
1365 - 1378
publisher
Elsevier
external identifiers
  • pmid:24954857
  • wos:000346215200001
  • scopus:84911959577
ISSN
1574-7891
DOI
10.1016/j.molonc.2014.05.008
language
English
LU publication?
yes
id
f5bac7e5-a1e1-4c26-9d4f-42db5645083d (old id 4527075)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24954857?dopt=Abstract
date added to LUP
2014-07-07 11:55:26
date last changed
2017-08-27 03:16:25
@article{f5bac7e5-a1e1-4c26-9d4f-42db5645083d,
  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.},
  author       = {Linnskog, Rickard and Jönsson, Gunilla and Axelsson, Lena and Prasad, Chandra and Andersson, Tommy},
  issn         = {1574-7891},
  language     = {eng},
  number       = {8},
  pages        = {1365--1378},
  publisher    = {Elsevier},
  series       = {Molecular Oncology},
  title        = {Interleukin-6 drives melanoma cell motility through p38α-MAPK-dependent up-regulation of WNT5A expression.},
  url          = {http://dx.doi.org/10.1016/j.molonc.2014.05.008},
  volume       = {8},
  year         = {2014},
}