Abrogation of the invasion of human bladder tumor cells by using protease inhibitor(s).
It was shown previously that invasive human transitional cell carcinoma cell line EJ, but not the noninvasive RT4 cells, can degrade basement membrane laminin and that the degradation of basement membrane laminin was a result of a redistribution of activated cysteine proteinase cathepsin B to the plasma membrane of the invasive EJ cells. Using a modified Boyden chamber and an artificial basement membrane, it was found first that cysteine proteinase inhibitor E-64 can abolish the ability of the EJ cells to invade through the artificial basement membrane to the underside of the filter. Second, E-64 can prevent the degradation of purified human basement membrane laminin by the plasma membrane fraction of invasive EJ cells. Third, E-64 does not affect the ability of the EJ cells to attach to the extracellular matrix nor is the inhibitory dose toxic to the cells when assayed with trypan-blue dye exclusion. However, E-64 does affect the ability of the EJ cells to respond to autocrine motility factor-induced motility. Finally, in an in vivo model, E-64 was not toxic to the animals tested and may have limited the blood-borne metastatic ability of invasive EJ cells in the treated animals. It was concluded that proteinase cathepsin B may be involved in human bladder tumor invasion, in both extracellular matrix degradation and factor-induced cellular motility, and the authors suggested that the use of inhibitor(s) to cysteine proteinases may limit the invasive potential of human bladder cancer cells.