Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis

Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dy sregulation of beta -catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, o verexpression of the integrin-linked kinase (ILK) has been shown to modulat e beta -catenin subcellular localization and function. However, the signifi cance of this finding for human carcinogenesis remains unclear. Here, we re port the increased biochemical activity and expression of ILK protein in po lyps from FAP patients. Furthermore, dramatic increases in ILK immunoreacti vity were observed in all abnormal crypts from sporadic polyps, when compar ed with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventati ve agents demonstrated in colorectal carcinogenesis, in both humans and ani mals, further investigation revealed that these non-steroidal antiinflammat ory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These includ e inhibition of, both the biochemical activation of ILK, inhibition of seri ne 9 GSK3 beta phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an earl y event in colonic polyposis. Additionally, ILK signaling is shown to under go modulation by sulindac (and aspirin) for the first time, indicating that it is likely to be one of the targets affected by these agents in vivo.