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Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Aug 14; Vol. 109 (33), pp. 13231-6. Date of Electronic Publication: 2012 Jul 31. - Publication Year :
- 2012
-
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.
- Subjects :
- Acetylserotonin O-Methyltransferase metabolism
Animals
Biocatalysis drug effects
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Cell Transformation, Neoplastic drug effects
Cyclooxygenase 2 Inhibitors pharmacology
Fibroblasts drug effects
Fibroblasts metabolism
Humans
Metabolic Networks and Pathways drug effects
Metabolomics
Mice
Neoplasm Metastasis
Solubility drug effects
Subcellular Fractions drug effects
Subcellular Fractions metabolism
Tryptophan biosynthesis
Tryptophan metabolism
Tryptophan pharmacology
Tryptophan Hydroxylase metabolism
Xenograft Model Antitumor Assays
Cell Transformation, Neoplastic pathology
Cyclooxygenase 2 metabolism
Tryptophan analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22851770
- Full Text :
- https://doi.org/10.1073/pnas.1209919109