title: Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan.
abstract: We reported previously that human fibroblasts release 5-methoxytryptophan (5-MTP) which inhibits cancer cell COX-2 overexpression and suppresses cancer cell migration and metastasis. To determine whether fibroblasts block cancer cell epithelial mesenchymal transition (EMT) via 5-MTP, we evaluated the effect of Hs68 fibroblasts (HsFb) on A549 cancer cell EMT in a two-chamber system. Co-incubation of A549 with HsFb prevented TGF-β1-induced reduction of E-cadherin and increase in Snail and N-cadherin. Transfection of HsFb with tryptophan hydroxylase-1 siRNA, which inhibited tryptophan hydroxylase-1 protein expression and 5-MTP release in HsFb abrogated the effect of HsFb on A549 EMT. Direct addition of pure 5-MTP to cultured A549 cells followed by TGF-β1 prevented TGF-β1-induced reduction of E-cadherin, and elevation of Snail, vimentin and matrix metalloproteinase 9. Administration of 5-MTP to a murine xenograft tumor model reduced vimentin protein expression in the tumor tissues compared to vehicle control which was correlated with reduction of metastasis in the 5-MTP treated mice. Our experimental data suggest that 5-MTP exerted its anti-EMT actions through inhibition of p38 MAPK activation, p65/p50 NF-κB nuclear translocation and transactivation without the involvement of COX-2 or p300 histone acetyltransferase. Our findings indicate that fibroblasts release a tryptophan metabolite, 5-MTP, to reduce cancer cell EMT, migration, invasion and metastasis.
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Huei-Hsuan
authors.initials: HH
authors.lastname: Cheng
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Chu
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Li-Yi
authors.initials: LY
authors.lastname: Chiang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.|Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
mesh_terms: D000072283:A549 Cells; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C027986:5-methoxytryptophan; D014364:Tryptophan; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 5-methoxytryptophan; epithelial mesenchymal transition; fibroblasts; lung cancer; tryptophan hydroxylase-1