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

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

  2. Author Address

    [Walther, W; Schlag, PM; Stein, U] Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany. [Scudiero, D; Selby, M] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Schlag, PM] Charite, Charite Comprehens Canc Ctr, D-10117 Berlin, Germany. [Shoemaker, RH] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA.;Stein, U (reprint author), Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany;ustein@mdc-berlin.de
    1. Year: 2011
    2. Date: Sep
  2. Journal: Molecular Biology of the Cell
    1. 22
    2. 18
    3. Pages: 3344-3354
  4. Type of Article: Article
  5. ISSN: 1059-1524
  1. 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 an 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, 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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External Sources

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  2. DOI: 10.1091/mbc.E10-09-0739
  3. View record in Web of Science®
  4. WOS: 000294823200006

Library Notes

  1. Fiscal Year: FY2011-2012
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