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J. Biol. Chem., Vol. 281, Issue 5, 2740-2749, February 3, 2006

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A Formylated Hexapeptide Ligand Mimics the Ability of Wnt-5a to Impair Migration of Human Breast Epithelial Cells^*

Annette Säfholm, Karin Leandersson, Janna Dejmek, Christian Kamp Nielsen, Bruno O. Villoutreix, and Tommy Andersson¹

From the Department of Laboratory Medicine, Experimental Pathology, Lund University, Malmö University Hospital, SE20502 Malmö, Sweden and INSERM U648, Structural Bioinformatics Team, University of Paris V, 4 Ave. de L'Observatoire, F75006 Paris, France

Loss of Wnt-5a protein expression is associated with shorter recurrence-free survival in breast carcinoma patients and increased motility in mammary cell lines. Based on sequence analysis of Wnt-5a, we identified 14 peptide fragments and investigated their ability to mimic the effects of Wnt-5a on mammary cell adhesion and migration. Two of these peptides significantly increased adhesion and impaired migration in the non-tumorigenic HB2 breast epithelial cell line and in the MDA-MB-468 breast cancer cell line, both of which show little endogenous expression of the Wnt-5a protein. We removed two amino acids at a time from the N terminus of the shorter of these two peptides to identify the shortest peptide that still inhibited migration. The influence on tumor cell adhesion was gradually lost and was no longer detectable when only six amino acids remained. However, formylation of the N-terminal methionine of this hexapeptide restored its effect on adhesion and reduced tumor cell motility via a Frizzled-5 receptor-dependent mechanism, even at a low pH such as encountered in breast tumor tissue. This formylated hexapeptide ligand induced a rapid cytosolic calcium signal, whereas it did not affect the cellular levels of unphosphorylated -catenin or active JNK. The novel formyl-Met-Asp-Gly-Cys-Glu-Leu peptide ligand is not only a valuable experimental tool but has also a potential role in antimetastatic treatment of the 50% of human breast cancer patients that have reduced endogenous Wnt-5a protein expression.

Received for publication, August 1, 2005 , and in revised form, November 30, 2005.

^* This work was supported by grants (to T. A.) from the Swedish Cancer Foundation, the Research School for Pharmaceutical Science (FLÄK), the Foundations at Malmö University Hospital, and Gunnar Nilsson's Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Experimental Pathology, Dept. of Laboratory Medicine, U-MAS, Entrance 78, Floor 3, SE-20502 Malmö, Sweden. Tel.: 46-40-337220; Fax: 46-40-337353; E-mail: tommy.andersson{at}med.lu.se.

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