Inhibition and mechanism of action of a protease inhibitor in human pancreatic cancer cells.
OBJECTIVE
Tumor-associated trypsinogen (TAT), urokinase-type plasminogen activator (u-PA), matrix metalloproteinase-2 (MMP-2), and MMP-9 each play a dominant role in the degradation of extracellular matrix (ECM) during the invasion process of pancreatic cancer. Transforming growth factor beta1 (TGF-beta1) is a multifunctional poly-peptide that regulates cell growth and differentiation, ECM deposition, cellular adhesion properties, angiogenesis, and also immune functions. We previously reported that TGF-beta1 up-regulated vascular endothelial growth factor (VEGF) production and protease production of MMP-2 and of u-PA in the highly metastatic pancreatic cancer cell lines SW1990 and CAPAN-2. In this study, we examined the inhibitor effects of a protease inhibitor, gabexate mesilate (GM), on cell invasion, cell proliferation, growth factor production, and ECM degradation. We also examined the effect of GM on the production of growth factor and ECM degradation by these cell proteases and enzymatic activities.


RESULTS
GM down-regulated the invasiveness and liver metastasis potential of SW1990 and CAPAN-2 cells, but it did not affect the proliferation of these cells. GM inhibited not only the enzymatic activities of TAT and u-PA but also the production of MMP-2, and u-PA, all of which have been known to be secondarily down-regulated by TGF-beta1.


CONCLUSIONS
These findings suggested that GM has very good potential for use in the treatment against invasion and metastasis of pancreatic cancer.
Uchima
Yasutake
Y
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Sawada
Tetsuji
T
Nishihara
Tamahiro
T
Maeda
Kiyoshi
K
Ohira
Masaichi
M
Hirakawa
Kosei
K
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D003094:Collagen; D004338:Drug Combinations; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D016670:Gabexate / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D004338:Drug Combinations; D007797:Laminin; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011509:Proteoglycans; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D016670:Gabexate; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9