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3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balanc...

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Detalles Bibliográficos
Autores principales: Ye, Fang, Chen, Shuang, Liu, Xingxing, Ye, Xiaohong, Wang, Keqi, Zeng, Zhiping, Su, Ying, Zhang, Xiao‐kun, Zhou, Hu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307790/
https://www.ncbi.nlm.nih.gov/pubmed/30370662
http://dx.doi.org/10.1111/jcmm.13900
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author Ye, Fang
Chen, Shuang
Liu, Xingxing
Ye, Xiaohong
Wang, Keqi
Zeng, Zhiping
Su, Ying
Zhang, Xiao‐kun
Zhou, Hu
author_facet Ye, Fang
Chen, Shuang
Liu, Xingxing
Ye, Xiaohong
Wang, Keqi
Zeng, Zhiping
Su, Ying
Zhang, Xiao‐kun
Zhou, Hu
author_sort Ye, Fang
collection PubMed
description Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules.
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spelling pubmed-63077902019-01-04 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation Ye, Fang Chen, Shuang Liu, Xingxing Ye, Xiaohong Wang, Keqi Zeng, Zhiping Su, Ying Zhang, Xiao‐kun Zhou, Hu J Cell Mol Med Original Articles Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules. John Wiley and Sons Inc. 2018-10-28 2019-01 /pmc/articles/PMC6307790/ /pubmed/30370662 http://dx.doi.org/10.1111/jcmm.13900 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Ye, Fang
Chen, Shuang
Liu, Xingxing
Ye, Xiaohong
Wang, Keqi
Zeng, Zhiping
Su, Ying
Zhang, Xiao‐kun
Zhou, Hu
3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title_full 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title_fullStr 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title_full_unstemmed 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title_short 3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation
title_sort 3‐cl‐ahpc inhibits pro‐hgf maturation by inducing matriptase/hai‐1 complex formation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307790/
https://www.ncbi.nlm.nih.gov/pubmed/30370662
http://dx.doi.org/10.1111/jcmm.13900
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