Abstract
Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of β-catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, overexpression of the integrin-linked kinase (ILK) has been shown to modulate β-catenin subcellular localization and function. However, the significance of this finding for human carcinogenesis remains unclear. Here, we report the increased biochemical activity and expression of ILK protein in polyps from FAP patients. Furthermore, dramatic increases in ILK immunoreactivity were observed in all abnormal crypts from sporadic polyps, when compared with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventative agents demonstrated in colorectal carcinogenesis, in both humans and animals, further investigation revealed that these non-steroidal anti-inflammatory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3β phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an early event in colonic polyposis. Additionally, ILK signaling is shown to undergo 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.
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Acknowledgements
This work was supported by grants from the Cancer Research Society and the Northwestern Society for Intestinal Research to B Salh, and from the National Cancer Institute to S Dedhar. We thank Stressgen (Victoria, BC) for generously providing anti-ILK, anti-PKB, anti-GSK3 and anti-CK2 antibodies, and Dr H Clevers for the TOPFLASH and TOPFLASH constructs.
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Marotta, A., Tan, C., Gray, V. et al. Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Oncogene 20, 6250–6257 (2001). https://doi.org/10.1038/sj.onc.1204791
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DOI: https://doi.org/10.1038/sj.onc.1204791
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