title: Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan.
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.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
authors.forename: Huei-Hsuan
authors.initials: HH
authors.lastname: Cheng
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
authors.forename: Jiann-Long
authors.initials: JL
authors.lastname: Yan
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Lin
authors.forename: Kai-Hsuan
authors.initials: KH
authors.lastname: Wang
authors.forename: Kelvin K-C
authors.initials: KK
authors.lastname: Tsai
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Guvén
authors.forename: Emilie
authors.initials: E
authors.lastname: Flaberg
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055432:Metabolomics; D051379:Mice; D009362:Neoplasm Metastasis; D012995:Solubility / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C027986:5-methoxytryptophan; D014364:Tryptophan; D014365:Tryptophan Hydroxylase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000121:Acetylserotonin O-Methyltransferase