Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis

Renhai Cao, Hua Lin Wu, Niina Veitonmäki, Philip Linden, Jacob Farnebo, Guey Yueh Shi, Yihai Cao

Research output: Contribution to journalArticlepeer-review

178 Citations (Scopus)

Abstract

Proteolytic enzymes are involved in generation of a number of endogenous angiogenesis inhibitors. Previously, we reported that angiostatin, a potent angiogenesis inhibitor, is a proteolytic fragment containing the first four kringle modules of plasminogen. In this report, we demonstrate that urokinase-activated plasmin can process plasminogen to release an angiogenesis inhibitor, K1-5 (protease-activated kringles 1-5). K1-5 inhibits endothelial-cell proliferation with a half-maximal concentration of approximately 50 pM. This inhibitory effect is endothelial-cell-specific and appears to be at least approximately 50-fold greater than that of angiostatin. A synergistic efficacy of endothelial inhibition was observed when angiostatin and kringle 5 (K5) were coincubated with capillary endothelial cells. The synergistic effect is comparable to that produced by K1-5 alone. Systemic treatment of mice with K1-5 at a low dose significantly blocked the fibroblast growth factor-induced corneal neovascularization, whereas angiostatin had no effect at the same dose. K1-5 also suppressed angiogenesis in chicken embryos. Systemic administration of K1-5 at a low dose at which angiostatin was ineffective significantly suppressed the growth of a murine T241 fibrosarcoma in mice. The antitumor effect correlates with the reduced neovascularization. These findings suggest that the plasmin- mediated proteolysis may be involved in the negative switch of angiogenesis.

Original languageEnglish
Pages (from-to)5728-5733
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number10
DOIs
Publication statusPublished - 1999 May 11

All Science Journal Classification (ASJC) codes

  • General

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