PNAS 2012-08-14

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 Szekely, George Klein, Kenneth K Wu

Index: Proc. Natl. Acad. Sci. U. S. A. 109(33) , 13231-6, (2012)

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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.