INHIBITION OF COLLAGENOLYTIC ACTIVITY AND METASTASIS OF TUMOR-CELLS BY A RECOMBINANT HUMAN TISSUE INHIBITOR OF METALLOPROTEINASES
INHIBITION OF COLLAGENOLYTIC ACTIVITY AND METASTASIS OF TUMOR-CELLS BY A RECOMBINANT HUMAN TISSUE INHIBITOR OF METALLOPROTEINASES
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DOI：
10.1093/jnci/82.7.589
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发表时间：
1990-04-04
影响因子：
10.3
通讯作者：
DECLERCK, YA
中科院分区：
文献类型：
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作者：
ALVAREZ, OA;CARMICHAEL, DF;DECLERCK, YA
由肿瘤细胞分泌的金属蛋白酶在转移中起重要作用。在本研究中，我们确定这些蛋白酶的抑制剂是否可以抑制肿瘤细胞降解胶原和转移的能力。具有I型胶原、IV型胶原、明胶和酪蛋白降解活性的金属蛋白酶由c-Ha-ras 1（也称为HRAS 1）转染的高转移性大鼠胚胎细胞系（4 R）分泌。这些金属蛋白酶经十二烷基硫酸钠底物-聚丙烯酰胺凝胶电泳鉴定为92千道尔顿和68千道尔顿的明胶分解酶和48千道尔顿和45千道尔顿的酪蛋白分解蛋白酶。重组人组织金属蛋白酶抑制剂（rTIMP）完全抑制这些酶的蛋白水解活性，也是一个有效的抑制剂的蛋白水解降解胶原蛋白的完整的c-Hra-ras 1转染细胞。当rTIMP重复腹腔注射到动物体内时，这些细胞在静脉注射到裸鼠体内后在肺中定殖的能力被抑制了83%。这些数据表明，rTIMP是这些细胞的金属蛋白酶活性的有效抑制剂，也可以抑制其转移潜力。
Metalloproteinases secreted by tumor cells play an important role in metastasis. In the present study, we determined whether an inhibitor of these proteinases could inhibit the ability of tumor cells to degrade collagen and to metastasize. Metalloproteinases with degradative activities for type I collagen, type IV collagen, gelatin, and casein were secreted by a highly metastatic rat embryo cell line (4R) transfected by c-Ha-ras1 (also known as HRAS1). These metalloproteinases were identified by sodium dodecyl sulfate substrate-polyacrylamide gel electrophoresis as 92-kilodalton and 68-kilodalton gelatinolytic enzymes and 48-kilodalton and 45-kilodalton caseinolytic proteinases. A recombinant human tissue inhibitor of metalloproteinases (rTIMP) completely inhibited the proteolytic activities of these enzymes and was also a potent inhibitor of the proteolytic degradation of collagen by intact c-Hra-ras1-transfected cells. The ability of these cells to colonize the lungs after intravenous injection into nude mice was inhibited by 83% when rTIMP was repeatedly injected intraperitoneally into the animals. These data demonstrate that rTIMP is a potent inhibitor of the metalloproteinase activities of these cells and can also inhibit their metastatic potential.