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A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion.

Jenei, Veronika; Sherwood, Victoria LU ; Howlin, Jillian LU ; Linnskog, Rickard LU ; Säfholm, Annette LU ; Axelsson, Lena LU and Andersson, Tommy LU (2009) In Proceedings of the National Academy of Sciences 106(46). p.19473-19478
Abstract
The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGFbeta1, controlled the expression of Wnt5a, but due to the unpredictable effects of... (More)
The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGFbeta1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGFbeta1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGFbeta1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca(2+) signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
106
issue
46
pages
19473 - 19478
publisher
National Acad Sciences
external identifiers
  • wos:000271907400046
  • pmid:19901340
  • scopus:73349119711
ISSN
1091-6490
DOI
10.1073/pnas.0909409106
language
English
LU publication?
yes
id
edcabd99-04f6-4a7e-8c89-792c45ee0815 (old id 1512101)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19901340?dopt=Abstract
date added to LUP
2009-12-01 15:22:54
date last changed
2017-11-12 04:08:06
@article{edcabd99-04f6-4a7e-8c89-792c45ee0815,
  abstract     = {The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGFbeta1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGFbeta1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGFbeta1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca(2+) signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers.},
  author       = {Jenei, Veronika and Sherwood, Victoria and Howlin, Jillian and Linnskog, Rickard and Säfholm, Annette and Axelsson, Lena and Andersson, Tommy},
  issn         = {1091-6490},
  language     = {eng},
  number       = {46},
  pages        = {19473--19478},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion.},
  url          = {http://dx.doi.org/10.1073/pnas.0909409106},
  volume       = {106},
  year         = {2009},
}