Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L-like proteases in tumor microenvironment
Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L-like proteases in tumor microenvironment
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DOI：
10.1158/1535-7163.mct-07-0528
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发表时间：
2008-03-01
影响因子：
5.7
通讯作者：
Scott, Christopher J.
中科院分区：
文献类型：
--
作者：
Burden, Roberta E.;Snoddy, Philip;Scott, Christopher J.
人组织蛋白酶 L 与组织蛋白酶 S、K 和 V 因其高度同源性而统称为组织蛋白酶 L 样蛋白酶。这些蛋白酶的过度表达和异常活性与肿瘤发生有关。这些蛋白酶含有前肽结构域，可以有效抑制其同源蛋白酶和组织蛋白酶 L 样亚家族中的其他蛋白酶。在这项研究中，我们重组生产了组织蛋白酶 S 前肽，并证明它是组织蛋白酶 L 样蛋白酶的肽分解、弹性蛋白分解和明胶分解活性的有效抑制剂。此外，我们还发现这种肽能够显着减弱一组人类癌细胞系中的肿瘤细胞侵袭。此外，IgG Fc 结构域与前肽 COOH 末端的融合产生了嵌合蛋白，其阻断肿瘤细胞侵袭的能力显着增强。与未修饰的前肽种类相比，该 Fc 融合蛋白在基于细胞的测定中表现出增强的稳定性。这种联合抑制组织蛋白酶 L 样蛋白酶的方法可能有助于进一步研究癌症和其他涉及其异常活性的疾病。此外，这种同时抑制多种半胱氨酸组织蛋白酶的策略可能代表了减弱肿瘤发生的新疗法的基础。
Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L-like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L-like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L-like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L-like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis.