A hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2 efficiently inhibits tumor cell invasion and metastasis.
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.
Wang
Xia
X
Department of Molecular Genetics, Shanghai Medical School, Fudan University, 200032 Shanghai, P.R. China. yszhu@shmu.edu.cn
Hou
Min
M
Tan
Li
L
Sun
Xinghui
X
Zhang
Yuqing
Y
Li
Ping
P
Zhu
Yunsong
Y
D000818:Animals; D018286:Carcinoma, Giant Cell / Q000473:pathology*; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010446:Peptide Fragments / Q000502:physiology; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D010446:Peptide Fragments; D017396:Plasminogen Activator Inhibitor 2; D011506:Proteins; D014568:Urokinase-Type Plasminogen Activator