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Intervening in beta-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis

Authors

  • U. Stein
  • F. Arlt
  • J. Smith
  • U. Sack
  • P. Herrmann
  • W. Walther
  • M. Lemm
  • I. Fichtner
  • R.H. Shoemaker
  • P.M. Schlag

Journal

  • Neoplasia

Citation

  • Neoplasia 13 (2): 131-144

Abstract

  • Colon cancer metastasis is often associated with activation of the Wnt/beta-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by beta-catenin and the importance of the interconnection of these cellular programs for metastasis. Here we probe the hypothesis that the nonsteroidal anti-inflammatory drug sulindac sulfide can inhibit colon cancer metastasis by intervening in beta-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type beta-catenin with sulindac. We analyzed sulindac's effects on beta-catenin expression and subcellular localization, beta-catenin binding to the T-cell factor (TCF)/S100A4 promoter complex, S100A4 promoter activity, S100A4 expression, cell motility, and proliferation. Mice intrasplenically transplanted with S100A4-overexpressing colon cancer cells were treated with sulindac. Tumor growth and metastasis, and their beta-catenin and S100A4 expressions, were determined. We report the expression knockdown of beta-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of beta-catenin to TCF was clearly lowered, resulting in reduced S100A4 promoter activity and expression. This correlated well with the inhibition of cell migration and invasion, which could be rescued by ectopic S100A4 expression. In mice, sulindac treatment resulted in reduced tumor growth in the spleen (P = .014) and decreased liver metastasis in a human colon cancer xenograft model (P = .025). Splenic tumors and liver metastases of sulindac-treated mice showed lowered beta-catenin and S100A4 levels. These results suggest that modulators of beta-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression.


DOI

doi:10.1593/neo.101172