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

Veronika Jenei, Victoria Sherwood, Jillian Howlin, Rickard Linnskog, Annette Säfholm, Lena Axelsson, Tommy Andersson

Research output: Contribution to journalArticle

90 Citations (Scopus)

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, TGF beta 1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGF beta 1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGF beta 1 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 Ca2+ 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.
Original languageEnglish
Pages (from-to)19473-19478
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume106
Issue number46
DOIs
Publication statusPublished - Nov 2009

Keywords

  • malignant melanoma
  • PROTEIN
  • GROWTH-FACTOR
  • MESENCHYMAL TRANSITION
  • CANCER
  • tumor cell invasion
  • TGF-BETA
  • inhibitory peptide
  • WNT5A EXPRESSION
  • WNT-5A
  • MIGRATION
  • MOTILITY
  • EPITHELIAL-CELLS
  • INHIBITION

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