Wang Yanyan, Wang Ye, An Song, Zhang Jinrui, Han Yuqian, Xu Jinge, Yu Fang, Yu Dahai, Fang Xuexun
School of Biological Engineering, Dalian Polytechnic University Dalian 116034 China.
Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, College of Life Science, Jilin University 2699 Qianjin Street Changchun 130012 P. R. China
RSC Adv. 2018 Apr 17;8(26):14347-14354. doi: 10.1039/c8ra00871j.
Matrix metalloproteinases (MMPs) are a family of Zn-containing and Ca-dependent proteases with vital roles in extracellular matrix remodeling. Deregulation of MMPs occurs in many pathological conditions such as cardiovascular diseases, inflammation, and cancer. The therapeutic potential of MMP inhibitors has been demonstrated in diseases such as arthritis and cancer. Here we demonstrated that the 3-valent lanthanide compounds LaCl, TbCl, GdCl, YbCl, and EuCl inhibit MMPs such as MMP-2, MMP-13, and MMP-14 (MT1-MMP). The inhibition is more potent and selective toward MT1-MMP compared to the other MMPs. EuCl was further selected to study the enzyme kinetics of the MT1-MMP inhibition. The results showed that the inhibition is a mixed type with anti-competition and non-competitive types, which indicated that inhibition was achieved by the compound bound to the non-active center of MT1-MMP and changing the enzyme conformation. The interaction between EuCl and MT1-MMP was further studied by UV-visible (UV-vis) light absorption. EuCl caused a slight blue shift of the maximum absorption wavelength of MT1-MMP, indicating the interaction reduced protein hydrophobicity. Moreover, EuCl exerted substantial inhibitory effects on the migration of HT-1080 cells. Thus, EuCl may play a role in modulating tumor cell behavior by inhibiting MMPs activities especially the MT1-MMP activity. These findings provide initial insight into the biological activity and potential therapeutic value of EuCl.
基质金属蛋白酶（MMPs）是一类含锌且依赖钙的蛋白酶家族，在细胞外基质重塑中发挥着至关重要的作用。MMPs的失调发生在许多病理状况下，如心血管疾病、炎症和癌症。MMP抑制剂在关节炎和癌症等疾病中的治疗潜力已得到证实。在此，我们证明了三价镧系化合物LaCl、TbCl、GdCl、YbCl和EuCl可抑制MMP-2、MMP-13和MMP-14（MT1-MMP）等MMPs。与其他MMPs相比，这种抑制对MT1-MMP更有效且更具选择性。进一步选择EuCl来研究MT1-MMP抑制的酶动力学。结果表明，该抑制作用为混合型，兼具反竞争性和非竞争性，这表明抑制作用是通过化合物与MT1-MMP的非活性中心结合并改变酶构象来实现的。通过紫外可见（UV-vis）光吸收进一步研究了EuCl与MT1-MMP之间的相互作用。EuCl使MT1-MMP的最大吸收波长发生轻微蓝移，表明这种相互作用降低了蛋白质的疏水性。此外，EuCl对HT-1080细胞的迁移具有显著的抑制作用。因此，EuCl可能通过抑制MMPs活性尤其是MT1-MMP活性在调节肿瘤细胞行为中发挥作用。这些发现为EuCl的生物活性和潜在治疗价值提供了初步见解。
