title: Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis.
abstract: Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of beta-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 beta-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 GSK3beta 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.
authors.affiliation: Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
authors.forename: A
authors.initials: A
authors.lastname: Marotta
authors.forename: C
authors.initials: C
authors.lastname: Tan
authors.forename: V
authors.initials: V
authors.lastname: Gray
authors.forename: S
authors.initials: S
authors.lastname: Malik
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: J
authors.initials: J
authors.lastname: Sanghera
authors.forename: B
authors.initials: B
authors.lastname: Dupuis
authors.forename: D
authors.initials: D
authors.lastname: Owen
authors.forename: S
authors.initials: S
authors.lastname: Dedhar
authors.forename: B
authors.initials: B
authors.lastname: Salh
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000201:enzymology* / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013467:Sulindac / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000099200:Scaffold Protein ILK
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D013467:Sulindac; D000099200:Scaffold Protein ILK