Cyclooxygenase-2 inhibition inhibits c-Met kinase activity and Wnt activity in colon cancer

Jurriaan B. Tuynman*, Louis Vermeulen, Elles M. Boon, Kristel Kemper, Aeilko H. Zwinderman, Maikel P. Peppelenbosch, Dirk J. Richel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Activity of receptor tyrosine kinases (RTK) in colorectal cancer (CRC) is associated with enhanced tumor growth and a poorer prognosis. In addition, cyclooxygenase-2 (COX-2) expression contributes to tumor growth and invasion. COX-2 inhibitors exhibit important anticarcinogenic potential against CRC, but the molecular mechanism underlying this effect and the relation with RTK signaling remain the subject of intense research effort. Therefore, the rapid effects of COX-2 inhibition in CRC on the complement of all cellular kinases were investigated using a kinase substrate peptide array, Western blotting, transfection, small interfering RNA assays, and CRC cell lines. The resulting alterations in the kinome profile revealed that celecoxib, a selective COX-2 inhibitor, impairs phosphorylation of substrates for the RTKs c-Met and insulinlike growth factor receptor, resulting in decreased downstream signaling. The decrease in c-Met activation is accompanied with an increase in glycogen synthase kinase 3β kinase activity together with a rapid increase in phosphorylation of β-catenin. In agreement, a significant reduction of β-catenin-T-cell factor-dependent transcription is observed both with celecoxib and selective inhibition of c-Met phosphorylation by small molecules. Hence, corepression of c-Met-related and β-catenin-related oncogenic signal transduction seems a major effector of celecoxib in CRC, which provides a rationale to use c-Met inhibitors and celecoxib analogous to target c-Met and Wnt signaling in a therapeutic setting for patients with CRC.

Original languageEnglish
Pages (from-to)1213-1220
Number of pages8
JournalCancer Research
Volume68
Issue number4
DOIs
Publication statusPublished - 15 Feb 2008

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