Yasutake Uchima, Tetsuji Sawada, Kosei Hirakawa
Tumor-associated trypsinogen, urokinase-type plasminogen activator, matrix metalloprotease- 2 (MMP-2), and MMP-9 each play a dominant role in the degradation of the extracellular matrix (ECM) during the invasion process of pancreatic cancer. Transforming growth factor beta1 (TGFbeta1) is a multifunctional polypeptide that regulates cell growth and differentiation, extracellular matrix deposition, cellular adhesion properties, angiogenesis and also immune functions. The protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor which is cleaved and activated by trypsin and tryptase. PAR-2 activated by trypsin plays an important role in promoting the proliferation of pancreatic cancer. We previously reported that TGF-beta1 upregulated vascular endothelial growth factor (VEGF) production, and the protease production of both MMP-2 and urokinasetype plasminogen activator in the highly metastatic pancreatic cancer cell lines SW1990 and CAPAN-2. We had examined the inhibitor effects of a protease inhibitor, gabexate mesilate, on cell invasion, cell proliferation, growth factor production, and ECM degradation. We also examined the effect of gabexate mesilate on the production of growth factor and ECM degradation by these cell proteases and enzymatic activities. Gabexate mesilate down-regulated the invasiveness, the proliferation and liver metastasis potential of SW1990 and CAPAN- 2 cells. Gabexate mesilate inhibited not only the enzymatic activities of tumor-associated trypsinogen and urokinase-type plasminogen activator but also the production of MMP-2, all of which have been known to be secondarily up-regulated by TGF-beta1. These findings suggested that gabexate mesilate is potentially useful in the treatment against invasion, proliferation, and metastasis of pancreatic cancer.