title: Intervening in β-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis.
abstract: Colon cancer metastasis is often associated with activation of the Wnt/β-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by β-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 β-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type β-catenin with sulindac. We analyzed sulindac's effects on β-catenin expression and subcellular localization, β-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 β-catenin and S100A4 expressions, were determined. We report the expression knockdown of β-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of β-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 β-catenin and S100A4 levels. These results suggest that modulators of β-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression.
authors.affiliation: Experimental and Clinical Research Center, Charité University Medicine, at the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. ustein@mdc-berlin.de
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
authors.forename: Franziska
authors.initials: F
authors.lastname: Arlt
authors.forename: Janice
authors.initials: J
authors.lastname: Smith
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sack
authors.forename: Pia
authors.initials: P
authors.lastname: Herrmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Walther
authors.forename: Margit
authors.initials: M
authors.lastname: Lemm
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Robert H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D013467:Sulindac / Q000627:therapeutic use*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C077591:S100A4 protein, human; D013467:Sulindac