國家衛生研究院 NHRI:Item 3990099045/8505
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    題名: Proliferating fibroblasts suppress cancer cell epithelial-to-mesenchymal transition (EMT) and migration via control inhibition of p300 HAT activation by 5-methoxytryptophan
    作者: Cheng, HH;Chang, TC;Chiang, LY;Kuo, CC;Wu, KK
    貢獻者: Institute of Cellular and Systems Medicine
    摘要: We recently identified 5-methoxytryptophan (5-MTP), a novel tryptophan metabolite, as an endogenous inhibitor of cyclooxygenase-2 (COX-2) expression. Our reported data show that cancer cells are defective in 5-MTP production and exogenous 5-MTP suppresses cancer cell COX-2 overexpression. Furthermore, 5-MTP inhibits cancer cell migration and invasion. However, it is unclear whether endogenous 5-MTP controls cancer cell COX-2 and COX-2 mediated cancer growth and metastasis. Since human proliferative fibroblasts (pFb) produce robust 5-MTP, we determined whether pFb controls cancer cell COX-2 expression and behavior. pFb co-cultured with A549 lung cancer cells in a two-chamber system inhibited PMA-induced COX-2 expression and migration in a time- and cell number-dependent manner. pFb blocked A549 epithelial mesenchymal transition (EMT) induced by transforming growth factor-β (TGFβ). Hydroxyindole O-methyltransferase (HIOMT) catalyzes the final step of 5-MTP synthesis. pFb expressed abundant HIOMT proteins. Knockdown of HIOMT in pFb resulted in abrogation of control of A549 COX-2 expression, migration and EMT in the two-chamber co-culture system. These results are consistent with control of A549 COX-2 expression and EMT/migration by 5-MTP. We next determined whether 5-MTP targets p300 histone acetyltransferase (HAT) which is essential for COX-2 transcriptional activation. Basal p300 HAT activity in A549 was stimulated by proinflammatory cytokines and phorbol esters, which was inhibited by 5-MTP. 5-MTP inhibited TGFβ. Co-cultured with pFb suppressed A549 p300 HAT, TGFβ and COX-2 which were abrogated by treating pFb with HIOMT siRNA. These findings suggest that fibroblasts control cancer cell COX-2 expression via inhibition of p300 HAT and TGFβ activation which results in suppression of cancer cell EMT and migration. Fibroblast produced 5-MTP may confer endogenous resistance to cancer growth and metastasis.
    日期: 2014-04
    關聯: FASEB Journal. 2014 Apr;28(1 Suppl.):Article number LB492.
    Link to: http://www.fasebj.org/content/28/1_Supplement/LB492.abstract?sid=fa8a1c00-f6b4-4f24-a155-25190a7aea39
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0892-6638&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000346651004433
    顯示於類別:[郭呈欽] 會議論文/會議摘要

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