基质蛋白酶是一种上皮特异性膜锚定的丝氨酸蛋白酶,它的失调与多种癌症的进展高度相关。肝细胞生长因子激活剂抑制剂-1(HAI-1)通过与激活的间质蛋白酶形成复合物来抑制间质蛋白酶活性。间质蛋白酶活化和间质蛋白酶/HAI-1复合物形成的平衡决定了间质蛋白酶活性的强度和持续时间。3-Cl-AHPC,4-[3-(1-金刚烷基)-4-羟基苯基]-3-氯肉桂酸,是金刚取代的类视黄醇相关分子和视黄酸受体γ(RARγ)的配体。3-Cl-AHPC具有很强的抗癌作用,但机制难以捉摸。在我们目前的研究中,我们显示,3-Cl-AHPC时间和剂量依赖性地诱导间质蛋白酶/HAI-1复合物的形成,导致抑制癌细胞和组织中的活化蛋白裂解酶。此外,3-Cl-AHPC促进基质蛋白酶脱落,但不增加脱落基质蛋白酶的活性。此外,3-Cl-AHPC通过间质蛋白酶/HAI-1复合物诱导抑制间质蛋白酶介导的pro-HGF裂解,导致抑制pro-HGF刺激的信号传导和细胞散射。尽管3-Cl-AHPC与RARγ结合,其对间质蛋白酶/HAI-1复合物的诱导不是RARγ依赖性的。一起,我们的数据表明,3-Cl-AHPC通过诱导间质蛋白酶/HAI-1复合物形成以RARγ-非依赖性方式下调间质蛋白酶活性,提供了一种3-Cl-AHPC抗癌活性的机制,并提供了一种使用小分子通过间质蛋白酶/HAI-1复合物诱导抑制异常间质蛋白酶活性的新策略。
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.