Locking Src/Abl tyrosine kinase activities regulate cell differentiation and invasion of human cervical cancer cells expressing E6/E7 oncoproteins of high-risk HPV

In this study,we compared the effects of ski-606 with iressa,src/abl and egf-r kinase inhibitors,respectively,on selected parameters in hela and siha cervical cancer cell lines,which express e6/e7 oncoproteins of high-risk hpv types 18 and 16,respectively. our results show that ski-606 and iressa inhibit cell proliferation and provoke g 0 - g 1 cell cycle arrest and reduction of s and g 2 -m phase using 2 and 5m concentrations of these inhibitors. in contrast,ski-606 induces differentiation to an epithelial phenotype mesenchymal- epithelial transition; thus ski-606 causes a dramatic decrease in cell motility and invasion abilities of hela and siha cancer cells,in comparison to untreated cells and iressa-treated cells in which these parameters are only slightly affected. these changes are accompanied by a regulation of the expression patterns of e-cadherin and catenins. the molecular pathway analysis of src/abl inhibitor revealed that ski-606 blocks the phosphorylation of -catenin and consequently converts its role from a transcriptional regulator to a cell-cell adhesion molecule. our findings indicate that ski-606 inhibits signaling pathways involved in regulating tumor cell migration and invasion genes via -catenin alteration,suggesting that src inhibitor,in comparison to egf-r,is a promising therapeutic agent for human cervical cancer. © 2010 amber yasmeen et al.