Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan.
Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan.
复制标题
DOI：
10.18632/oncotarget.9111
复制
发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Wu KK
中科院分区：
文献类型：
--
作者：
Cheng HH;Chu LY;Chiang LY;Chen HL;Kuo CC;Wu KK
我们以前报道过人成纤维细胞释放5-甲氧基色氨酸（5-MTP），它抑制癌细胞考克斯-2的过度表达，并抑制癌细胞的迁移和转移。为了确定成纤维细胞是否通过5-MTP阻断癌细胞上皮间质转化（EMT），我们在双室系统中评估了Hs 68成纤维细胞（HsFb）对A549癌细胞EMT的影响。A549与HsFb共孵育可阻止TGF-β1诱导的E-cadherin减少以及Snail和N-cadherin增加。用色氨酸羟化酶-1 siRNA转染HsFb，抑制HsFb中色氨酸羟化酶-1蛋白表达和5-MTP释放，消除了HsFb对A549 EMT的作用。直接向培养的A549细胞中加入纯的5-MTP，然后加入TGF-β1，可防止TGF-β1诱导的E-钙粘蛋白的减少，以及Snail、波形蛋白和基质金属蛋白酶9的升高。与媒介物对照相比，向鼠异种移植肿瘤模型施用5-MTP减少了肿瘤组织中的波形蛋白蛋白表达，这与5-MTP处理的小鼠中转移的减少相关。实验结果表明，5-MTP通过抑制p38 MAPK活化、p65/p50 NF-κB核转位和转录激活发挥抗EMT作用，而不涉及考克斯-2或p300组蛋白乙酰转移酶。我们的研究结果表明，成纤维细胞释放色氨酸代谢产物5-MTP，以减少癌细胞的EMT，迁移，侵袭和转移。
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.
登录
查看更多内容
影响因子：
8.8
作者：
Adhim, Z.;Matsuoka, T.;Bito, T.;Shigemura, K.;Lee, K-M;Kawabata, M.;Fujisawa, M.;Nibu, K.;Shirakawa, T.
通讯作者：
Shirakawa, T.
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
3.7
作者：
Cheng, Huei-Hsuan;Wang, Kai-Hsuan;Wu, Kenneth K.
通讯作者：
Wu, Kenneth K.
影响因子：
5.8
作者：
Bocca, Claudia;Ievolella, Monica;Miglietta, Antonella
通讯作者：
Miglietta, Antonella
DOI：
10.1155/2012/289243
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Gui T;Sun Y;Shimokado A;Muragaki Y
通讯作者：
Muragaki Y