The
urokinase plasminogen activator(uPA) system plays important roles in
tumor cell invasion and
metastasis. In the present study, we evaluated the effects of ATF-PAI2CD, a hybrid
protein of the amino-terminal fragment of
urokinase and mutant
plasminogen activator inhibitor-2, on 95D cells in vitro and in vivo. Furthermore, our results support a current hypothesis that fusion
protein blocks
tumor invasion and motility by inhibiting localized pericellular proteolysis. Treatment of 95D cells with ATF-PAI2CD resulted in a dose-dependent decrease in
tumor-cell invasion through
matrigel, and ATF-PAI2CD was much more effective than PAI-2CD. In addition, extracellular regular
protein kinase (ERK1/2) expression was downregulated and the adhesion ability to
fibronectin was increased in 95D cells treated with the fusion
protein, which was confirmed by cell adhesion assay. A high-concentration of ATF-PAI2CD caused a significant reduction in
tumor volume and weight in BALB/c (nu/nu) mice female inoculated with human 95D cells (5 x 10(6)); the antitumor effects were significant, which demonstrated a 67.9+/-4.2% reduction in
tumor growth compared with control mice. The number of
lymphatic metastasis was significantly reduced in mice treated with high- and middle- concentrations of ATF-PAI2CD, whereas a low-concentration of ATF-PAI2CD failed to exhibit any antimetastatic effects. In conclusion, the results suggested that the hybrid
protein has therapeutic potential for lung
carcinoma and other
tumors to inhibit
tumor invasion and
metastasis.