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

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 Szekelyd, George Klein, Kenneth K. Wu

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39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13231-13236
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number33
DOIs
Publication statusPublished - Aug 14 2012
Externally publishedYes

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Keywords

  • Inflammation control
  • Tryptophan metabolism
  • Tumor suppression

ASJC Scopus subject areas

  • General

Cite this

Cheng, H. H., Kuo, C. C., Yan, J. L., Chen, H. L., Lin, W. C., Wang, K. H., Tsai, K. K. C., Guvén, H., Flaberg, E., Szekelyd, L., Klein, G., & Wu, K. K. (2012). Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. Proceedings of the National Academy of Sciences of the United States of America, 109(33), 13231-13236. https://doi.org/10.1073/pnas.1209919109