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

研究成果: 雜誌貢獻文章

40 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)13231-13236
頁數6
期刊Proceedings of the National Academy of Sciences of the United States of America
109
發行號33
DOIs
出版狀態已發佈 - 八月 14 2012
對外發佈Yes

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    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