Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy.
Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy.
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发表时间：
2003-06
期刊：
影响因子：
11.2
通讯作者：
Cheng Liu;Chengzao Sun;Haining Huang;K. Janda;T. Edgington
中科院分区：
文献类型：
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作者：
Cheng Liu;Chengzao Sun;Haining Huang;K. Janda;T. Edgington
通过基因表达谱和肿瘤组织阵列分析，确定了一种新的天冬酰胺内肽酶legumain在肿瘤中的表达。豆科蛋白存在于肿瘤细胞的膜相关囊泡中，这些囊泡集中在肿瘤细胞的侵足部和与整合素共定位的细胞表面。结果表明，过表达豆类蛋白的细胞在体外具有迁移和侵袭活性增强，在体内表现为侵袭性和转移性表型，提示豆类蛋白在肿瘤侵袭转移中的重要作用。开发了一种将豆类可切割肽底物结合到阿霉素上的前药策略。在小鼠结肠癌模型中，这种原型化合物被命名为豆蔻霉素，表现出较低的毒性和有效的杀瘤作用。
Expression of legumain, a novel asparaginyl endopeptidase, in tumors was identified from gene expression profiling and tumor tissue array analysis. Legumain was demonstrated in membrane-associated vesicles concentrated at the invadopodia of tumor cells and on cell surfaces where it colocalized with integrins. Legumain was demonstrated to activate progelatinase A. Cells overexpressing legumain possessed increased migratory and invasive activity in vitro and adopted an invasive and metastatic phenotype in vivo, inferring significance of legumain in tumor invasion and metastasis. A prodrug strategy incorporating a legumain-cleavable peptide substrate onto doxorubicin was developed. The prototype compound, designated legubicin, exhibited reduced toxicity and was effectively tumoricidal in vivo in a murine colon carcinoma model.