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Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13231-6. doi: 10.1073/pnas.1209919109. Epub 2012 Jul 31.

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan.

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  • 1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.

Abstract

Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.

PMID:
22851770
[PubMed - indexed for MEDLINE]
PMCID:
PMC3421199
Free PMC Article
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