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SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of ß-Catenin and Its Nuclear Signaling

¹ Department of Experimental Oncology, National Cancer Institute, Milan, Italy; ² McGill University, Montreal, Quebec, Canada; and ³ Department of Clinical Medicine, S. Gerardo Hospital-University of Milano-Bicocca, Monza, Italy

Requests for reprints: Addolorata Maria Luce Coluccia, Department of Clinical Medicine, S. Gerardo Hospital-University of Milano-Bicocca, via Cadore 48, 20052 Monza, Italy. Phone: 39-2-64488059; Fax: 39-2-64488363; E-mail: coluccia{at}istitutotumori.mi.it or malu.coluccia{at}unimib.it.

Inhibition of deregulated protein tyrosine kinases represents an attractive strategy for controlling cancer growth. However, target specificity is an essential aim of this strategy. In this report, pp60(c-Src) kinase and ß-catenin were found physically associated and constitutively activated on tyrosine residues in human colorectal cancer cells. The use of specific small-interfering RNAs (siRNA) validated pp60(c-Src) as the major kinase responsible for ß-catenin tyrosine phosphorylation in colorectal cancer. Src-dependent activation of ß-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated ß-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its trans-activating ability in colorectal cancer cells. These effects were seemingly specific, as cyclin D1, a crucial ß-catenin/TCF4 target gene, was also down-regulated by SKI-606 in a dose-dependent manner accounting, at least in part, for the reduced growth (IC₅₀, 1.5-2.4 µmol/L) and clonogenic potential of colorectal cancer cells. Protein levels of ß-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of ß-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining. The SKI-606-mediated relocalization of ß-catenin increased its binding affinity to E-cadherin and adhesion of colorectal cancer cells, with ensuing reduced motility in a wound healing assay. Interestingly, the siRNA-driven knockdown of ß-catenin removed the effect of SKI-606 on cell-to-cell adhesion, which was associated with prolonged stability of E-cadherin protein in a pulse-chase experiment. Thus, our results show that SKI-606 operates a switch between the transcriptional and adhesive function of ß-catenin by inhibiting its pp60(c-Src)–dependent tyrosine phosphorylation; this could constitute a new therapeutic target in colorectal cancer. (Cancer Res 2006; 66(4): 2279-86)

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