Regulation Of Matriptase Activation And Cancer Cell Migration And Invasion By 3-Cl-AHPC

Nuclear receptors are one of the most abundant classes of transcriptional regulators in animals,which play an important role in many diseases like cancer with underlying molecular mechanism.3-Cl-AHPC,4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid,is an adamantly-substituted retinoid related molecule,which was originally identified as a ligand of retinoic acid receptor gamma(RARy).3-ClAHPC has received extensive attension due to its potent anti-cancer activities.However,the underlying molecular mechanism of 3-Cl-AHPC remain elusive as both RARy-dependent and-independent anti-cancer effects have been reported.Matriptase is an epithelia-specific membrane-anchored serine protease,and its dysregulation is involved in the progression of a variety of cancers.Matriptase is a zymogen that can be converted into an active enzyme through autoactivation.Hepatocyte growth factor activator inhibitor-1(HAI-1)acts as the cognate inhibitor of matriptase by forming complex with activated matriptase.In our current study,we showed that 3-Cl-AHPC could time-and dose-dependently induce matriptase/HAI-1 complex formation,leading to suppression of activated matriptase in cancer cells and tissues.Furthermore,3-Cl-AHPC promoted matriptase shedding without increasing the net activity of shedding matriptase.Moreover,we found that 3-Cl-AHPC could inhibit matriptase-mediated cleavage of pro-HGF(hepatocyte growth factor)through induction of matriptase/HAI-1 complex,which led to suppression of pro-HGF-stimulated signaling transduction and inhibition of cancer cell migration and invasion.Together,our results demonstrate a new mechanism by which 3-Cl-AHPC exerts its anti-cancer effects and provide new strategies to identify and develop matriptase inhibitors for cacner therapy.