SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling

Cancer Res. 2006 Feb 15;66(4):2279-86. doi: 10.1158/0008-5472.CAN-05-2057.


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 beta-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 beta-catenin tyrosine phosphorylation in colorectal cancer. Src-dependent activation of beta-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated beta-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 beta-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 micromol/L) and clonogenic potential of colorectal cancer cells. Protein levels of beta-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of beta-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining. The SKI-606-mediated relocalization of beta-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 beta-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 beta-catenin by inhibiting its pp60(c-Src)-dependent tyrosine phosphorylation; this could constitute a new therapeutic target in colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Cadherins / metabolism
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Humans
  • Intercellular Junctions / drug effects
  • Nitriles / pharmacology*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects
  • TCF Transcription Factors / metabolism
  • Transcription Factor 7-Like 2 Protein
  • Transcriptional Activation / drug effects
  • Tyrosine / metabolism
  • beta Catenin / metabolism*


  • Aniline Compounds
  • Cadherins
  • Nitriles
  • Quinolines
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin
  • Tyrosine
  • bosutinib
  • Proto-Oncogene Proteins pp60(c-src)