Oncotarget

Research Papers:

Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan

Huei-Hsuan Cheng, Ling-Yun Chu, Li-Yi Chiang, Hua-Ling Chen, Cheng-Chin Kuo and Kenneth K. Wu _

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Oncotarget. 2016; 7:31243-31256. https://doi.org/10.18632/oncotarget.9111

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Abstract

Huei-Hsuan Cheng1,2,*, Ling-Yun Chu1,*, Li-Yi Chiang1, Hua-Ling Chen3, Cheng-Chin Kuo2,3, Kenneth K. Wu1,2,3,4

1Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan

2Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

3Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan

4Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan

*These authors contributed equally to this work

Correspondence to:

Kenneth K. Wu, email: [email protected]

Huei-Hsuan Cheng, email: [email protected]

Keywords: epithelial mesenchymal transition, fibroblasts, lung cancer, 5-methoxytryptophan, tryptophan hydroxylase-1

Received: January 29, 2016     Accepted: April 11, 2016     Published: April 29, 2016

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.


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