Journal
ONCOTARGET
Volume 7, Issue 21, Pages 31243-31256Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9111
Keywords
epithelial mesenchymal transition; fibroblasts; lung cancer; 5-methoxytryptophan; Tryptophan hydroxylase-1
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Funding
- Ministry of Science and Technology Excellent Research Team Program [NSC 102-2321-B-039-009]
- Stem Cell Frontier Program [NSC 102-2321-B-400-012]
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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-beta 1-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-beta 1 prevented TGF-beta 1-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-kappa B 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.
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