S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell

Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
Molecular biology of the cell (Impact Factor: 4.47). 07/2011; 22(18):3344-54. DOI: 10.1091/mbc.E10-09-0739
Source: PubMed


The calcium-binding protein S100A4 is a central mediator of metastasis formation in colon cancer. S100A4 is a target gene of the Wnt/β-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 an S100A4-specific manner. Calcimycin reduced β-catenin mRNA and protein levels despite the expression of Δ45-mutated β-catenin. Consequently, calcimycin inhibited Wnt/β-catenin pathway activity and the expression of prominent β-catenin target genes such as S100A4, cyclin D1, c-myc, and dickkopf-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 for studying S100A4 biology, and these studies may serve as a lead for the development of treatments for colon cancer metastasis.

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    • "Irrespective of the intracellular p53 status, S100A4 levels increase parallel to the number of epithelial cells in the S phase (107). In this regard, calcimycin, a calcium ionophore and transcriptional inhibitor of S100A4, restricts cell motility in CRC cells and inhibits metastasis formation in the intrasplenic HCT116 xenograft mouse model (120). The very same research group also identified that niclosamide, which is an established antihelminthic drug, may act as a potential therapy against S100A4-mediated metastatic colon tumors (121). "
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