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 journalArticle

34 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

Fingerprint

Cyclooxygenase 2
Carcinogenesis
Neoplasms
Tryptophan
Acetylserotonin O-Methyltransferase
Tryptophan Hydroxylase
Metabolomics
5-methoxytryptophan
Immunoenzyme Techniques
Heterografts
Anti-Inflammatory Agents
Fibroblasts
Neoplasm Metastasis
Inflammation
Growth
Pharmaceutical Preparations

Keywords

  • Inflammation control
  • Tryptophan metabolism
  • Tumor suppression

ASJC Scopus subject areas

  • General

Cite this

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. / Cheng, Huei Hsuan; Kuo, Cheng Chin; Yan, Jiann Long; Chen, Hua Ling; Lin, Wei Chung; Wang, Kai Hsuan; Tsai, Kelvin K C; Guvén, Hayrettin; Flaberg, Emilie; Szekelyd, Laszlo; Klein, George; Wu, Kenneth K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 33, 14.08.2012, p. 13231-13236.

Research output: Contribution to journalArticle

Cheng, HH, Kuo, CC, Yan, JL, Chen, HL, Lin, WC, Wang, KH, Tsai, KKC, Guvén, H, Flaberg, E, Szekelyd, L, Klein, G & Wu, KK 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, vol. 109, no. 33, pp. 13231-13236. https://doi.org/10.1073/pnas.1209919109
Cheng, Huei Hsuan ; Kuo, Cheng Chin ; Yan, Jiann Long ; Chen, Hua Ling ; Lin, Wei Chung ; Wang, Kai Hsuan ; Tsai, Kelvin K C ; Guvén, Hayrettin ; Flaberg, Emilie ; Szekelyd, Laszlo ; Klein, George ; Wu, Kenneth K. / Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 33. pp. 13231-13236.
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