1. Academic Validation
  2. 3-Cl-AHPC inhibits pro-HGF maturation by inducing matriptase/HAI-1 complex formation

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

  • J Cell Mol Med. 2019 Jan;23(1):155-166. doi: 10.1111/jcmm.13900.
Fang Ye 1 Shuang Chen 1 Xingxing Liu 1 Xiaohong Ye 1 Keqi Wang 1 Zhiping Zeng 1 Ying Su 1 2 Xiao-Kun Zhang 1 2 Hu Zhou 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
  • 2 Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Abstract

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.

Keywords

3-Cl-AHPC; HAI-1; HGF; RARγ; complex; matriptase; pro-HGF.

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