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S100A4-induced cell motility and metastasis is restricted by the Wnt/β-catenin pathway inhibitor calcimycin in colon cancer cells

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Item Type:Article
Title:S100A4-induced cell motility and metastasis is restricted by the Wnt/β-catenin pathway inhibitor calcimycin in colon cancer cells
Creators Name:Sack, U. and Walther, W. and Scudiero, D. and Selby, M. and Aumann, J. and Lemos, C. and Fichtner, I. and Schlag, P.M. and Shoemaker, R.H. and Stein, U.
Abstract:The calcium-binding protein S100A4 is a central mediator of metastasis formation in colon cancer. S100A4 is a target gene of the Wnt/{beta}-catenin pathway, which is constitutively active in the majority of colon cancers. In this study a high throughput screen was performed to identify small molecule compounds targeting the S100A4-promoter activity. In this screen calcimycin was identified as a transcriptional inhibitor of S100A4. In colon cancer cells calcimycin treatment reduced S100A4 mRNA and protein expression in a dose- and time-dependent manner. S100A4-induced cellular processes associated with metastasis formation, such as cell migration and invasion were inhibited by calcimycin in a S100A4-specific manner. Calcimycin reduced {beta}-catenin mRNA and protein levels despite the expression of {Delta}45-mutated {beta}-catenin. Consequently, calcimycin inhibited Wnt/{beta}-catenin pathway activity and the expression of prominent {beta}-catenin target genes such as S100A4, CyclinD1, c-myc, and DKK-1. Finally, calcimycin treatment of human colon cancer cells inhibited metastasis formation in xenografted immunodeficient mice. Our results demonstrate that targeting the expression of S100A4 with calcimycin provides a functional strategy to restrict cell motility in colon cancer cells. Therefore, calcimycin may be useful to study S100A4 biology and these studies may serve as a lead for the development of treatments for colon cancer metastasis.
Keywords:Calcimycin, S100A4, Wnt/beta-Catenin Pathway, Colon Cancer, Metastasis, Animals, Mice
Source:Molecular Biology of the Cell
ISSN:1059-1524
Publisher:American Society for Cell Biology (U.S.A.)
Volume:22
Number:18
Page Range:3344-3354
Date:September 2011
Official Publication:https://doi.org/10.1091/mbc.E10-09-0739
PubMed:View item in PubMed

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