Document Detail


Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan.
MedLine Citation:
PMID:  22851770     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Huei-Hsuan Cheng; Cheng-Chin Kuo; Jiann-Long Yan; Hua-Ling Chen; Wei-Chung Lin; Kai-Hsuan Wang; Kelvin K-C Tsai; Hayrettin Guvén; Emilie Flaberg; Laszlo Szekely; George Klein; Kenneth K Wu
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-31
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-15     Completed Date:  2012-10-29     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13231-6     Citation Subset:  IM    
Affiliation:
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Acetylserotonin O-Methyltransferase / metabolism
Animals
Biocatalysis / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Transformation, Neoplastic / drug effects,  pathology*
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / pharmacology
Fibroblasts / drug effects,  metabolism
Humans
Metabolic Networks and Pathways / drug effects
Metabolomics
Mice
Neoplasm Metastasis
Solubility / drug effects
Subcellular Fractions / drug effects,  metabolism
Tryptophan / analogs & derivatives*,  biosynthesis,  metabolism,  pharmacology
Tryptophan Hydroxylase / metabolism
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Cyclooxygenase 2 Inhibitors; 2504-22-5/5-methoxytryptophan; 73-22-3/Tryptophan; EC 1.14.16.4/Tryptophan Hydroxylase; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 2.1.1.4/Acetylserotonin O-Methyltransferase
Comments/Corrections

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