Recombinant human prothrombin kringle-2 inhibits B16F10 melanoma metastasis through inhibition of neovascularization and reduction of matrix metalloproteinase expression.
Angiogenesis, a multi-step process which involves endothelial cell proliferation, adhesion, migration, and basement membrane (BM) degradation, is essential for tumor metastasis. Here we show that recombinant human prothrombin kringle-2 (rk-2) inhibited bovine capillary endothelial cell migration with an IC(50) (concentration for half maximal inhibition) of 38 nM and inhibited adhesion to extracellular matrix (ECM) proteins. Because tumor metastasis requires angiogenesis, we examined whether rk-2 could inhibit metastases induced by injection of B16F10 melanoma cells into mice. The results revealed that the metastatic tumors in mouse lung were markedly decreased in a dose-dependent manner and acute lung injury induced by B16F10 melanoma metastasis was diminished by systemic rk-2 treatment. In immunohistochemical analysis, rk-2 reduced expression of vascular endothelial growth factor, which is a potent angiogenic activator and neovascularization in the mouse lung. Also, rk-2 diminished the expression of matrix metalloproteinase-2 and -9 in the mouse lung which induces tumor metastasis and angiogenesis. These data suggest that inhibition of B16F10 melanoma metastasis by rk-2 was caused by inhibition of neovascularization and reduction of matrix metalloproteinase expression.
Kim
Tae Hyong
TH
Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea.
Ahn
Sookyung
S
Kim
Jaebeum
J
Kim
Ilhan
I
Yang
Mei Zi
MZ
Lee
Jong Eun
JE
Kim
Soung Soo
SS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D018082:Kringles; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary; D011516:Prothrombin / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D011516:Prothrombin