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

Sack, U.; Walther, W.; Scudiero, D.; Selby, M.; Aumann, J.; Lemos, C.; Fichtner, I.; Schlag, P.M.; Shoemaker, R.H.; Stein, U.

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., Walther, W., Scudiero, D., Selby, M., Aumann, J., Lemos, C., Fichtner, I., Schlag, P.M., 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
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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