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

Research output: Contribution to journalArticlepeer-review

43 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

Keywords

  • Inflammation control
  • Tryptophan metabolism
  • Tumor suppression

ASJC Scopus subject areas

  • General

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