Work from many laboratories has demonstrated that protease inhibitors are effective suppressors of carcinogenesis in vitro and in vivo; in our laboratory, we have previously observed that the soybean derived Bowman-Birk protease inhibitor (BBI) prevents or suppresses carcinogenesis in the mouse colon and lung and the hamster cheek pouch. Although the mechanisms by which protease inhibitors suppress carcinogenesis are not fully understood, we believe these compounds expert their anticarcinogenic effects by inhibiting cellular proteases involved in the expression and/or induction of the transformed phenotype. Therefore, protease inhibitors are useful tools to identify proteases which may be involved in carcinogenesis. The goals of this research are to gain a better understanding of the roles that specific proteases may play in carcinogenesis and normal cell physiology. In the proposed studies, we will: 1) Isolate and fully characterize a particular protease from hamster check pouch, mouse colonic epithelium and mouse lung which cleaves the substrate Boc-Val-Pro-Arg-MCA and is inhibited by the BBI. We believe this protease is involved in carcinogenesis. 2) Determine whether this protease, or any other proteases, are persistently induced following carcinogen treatment of the colon and lung and determine whether and induced proteases in these tissues are BBI- inhibitable. We have previously reported that the particular protease described above is persistently induced in the hamster cheek pouch epithelium (i.e., the Boc-Val-Pro-Arg-MCA hydrolyzing activity increased about 10-fold in normal appearing areas of dimethylbenzanthracene-treated hamster cheek pouch epithelium). The persistent induction of a specific protease (or proteases) in carcinogen treated cells may well provide a marker to identify initiated cells.
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