Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells
Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells
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DOI：
10.1002/ijc.10977
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发表时间：
2003-05-01
影响因子：
6.4
通讯作者：
Strongin, AY
中科院分区：
文献类型：
--
作者：
Deryugina, EI;Ratnikov, BI;Strongin, AY
膜1型基质金属蛋白酶（MT1-MMP）和α β 3整合素直接参与肿瘤细胞的播散和转移。我们已经证明，在乳腺癌MCF7细胞共表达MT1-MMP和α - β 3整合素的情况下，蛋白酶加工α - β 3整合素前亚基，从而促进α - β 3整合素的成熟和细胞在玻璃体连接蛋白上的迁移。我们的研究结果表明，细胞表面MT1-MMP是一种寿命较短的蛋白质，其寿命在几个小时的范围内。相比之下，α β 3整合素的周转要慢得多。α β 3异源二聚体的半衰期约为24小时。这种寿命上的巨大差异使我们能够区分MT1-MMP对基质蛋白水解带来的细胞迁移的影响和通过α β 3整合素成熟施加的影响。然后，我们通过一种有效的羟酸盐MMP抑制剂Prinomastat （AG3340）来调节酶的活性，以分析MT1-MMP对细胞迁移的不同影响。尽管Prinomastat立即阻断了mt1 - mmp介导的基质降解，但mt1 - mmp修饰的alphavbeta3整合素分子池仍然能够介导细胞-基质相互作用。令我们相当惊讶的是，Prinomastat抑制MT1-MMP依赖的玻璃体连接蛋白水解，使得共同表达MT1-MMP和α β 3整合素的MCF7细胞的迁移增加了几倍。相比之下，长期的Prinomastat抑制mt1 - mmp依赖性的α - β - 3前分裂和α - β - 3整合素成熟强烈地抑制了细胞运动。我们的研究表明，MT1-MMP实际上可以通过修饰细胞表面受体（包括alphavbeta3整合素）来促进细胞迁移，而不是通过直接切割基质蛋白来促进细胞迁移。(C) 2003 Wiley-Liss, Inc。
Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have demonstrated that in the case of breast carcinoma MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin, the proteinase processes the pro-alphav integrin subunit, thus facilitating alphavbeta3 integrin maturation and cell migration on vitronectin. Our findings show that cell surface MT1-MMP is a short-lived protein with a life span in the range of several hours. In contrast, turnover of alphavbeta3 integrin is much slower. The half-life of alphavbeta3 heterodimer is about 24 hr. This large difference in life span allowed us to distinguish between the effects of MT1-MMP on cell migration brought by matrix proteolysis from those imposed through alphavbeta3 integrin maturation. We then modulated the enzyme's activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze the divergent effects of MT1-MMP on cell migration. Although Prinomastat immediately blocked MT1-MMP-mediated matrix degradation, the pool of MT1-MMP-modified alphavbeta3 integrin molecules was still capable of mediating cell-matrix interactions. To our considerable surprise, inhibition of MT1-MMP-dependent vitronectin proteolysis by Prinomastat allowed a several-fold increase in migration of MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin. In contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell motility. Our studies suggest that MT1-MMP could actually promote cell migration via modification of the cell surface receptors, including alphavbeta3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins. (C) 2003 Wiley-Liss, Inc.