Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail,in APC-/- human colon carcinoma cells

Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic beta -catenin and activation of genes that are r esponsive to Lef/Tcf family transcription factors. We have recently shown t hat an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate beta -catenin/LEF mediated gene transcription an d downregulate E-cadherin expression. In addition, ILK activity and express ion are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited IL K activity in APC-/- human colon carcinoma cell lines. In all cases, inhibi tion of ILK resulted in substantial inhibition of TCF mediated gene transcr iption and inhibition of transcription and expression of the TCF regulated gene, cyclin D1, Inhibition of ILK resulted in decreased nuclear beta-caten in expression, and in the inhibition of phosphorylation of GSK-3 and stimul ation of its activity, leading to accelerated degradation of beta -catenin. In addition, inhibition of ILK suppressed cell growth in culture as well a s growth of human colon carcinoma cells in SCID mice. Strikingly, inhibitio n of ILK also resulted in the transcriptional stimulation of E-cadherin exp ression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a s timulation of expression of snail, but snail expression was found not to be regulated by beta -catenin/ Tcf, These data demonstrate that ILK can regul ate beta -catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas.