There is increasing evidence that malignant progression of human tumors involves proteolytic cascades that are initiated at the tumor cell surface. Two major observations implicate the lysosomal cysteine protease cathepsin B in this process. One is that cathepsin B becomes a cell surface enzyme in tumors. The other is that high levels of expression of cathepsin B correlate positively with aggressive behavior and progression of human tumors and negatively with patient survival. Cathepsin B appears to be a participant as cathepsin B inhibitors and cysteine protease inhibitors reduce tumor cell motility, invasion and growth in vitro and tumor growth and metastasis in vivo. Recent studies have found that cathepsin B expression is dramatically increased in premalignant lesions. This would be consistent with our hypothesis that membrane-associated cathepsin B degrades basement membrane coincident with the transition to malignancy. In this proposal, we will evaluate mechanisms that may result in association of cathepsin B with the tumor cell surface and, using model systems for colon cancer, determine whether this protease participates in degradation of extracellular matrix proteins and invasion in vitro and malignant progression in vivo. In the first aim, we will establish the function of various regions of cathepsin B in its trafficking using cells deficient in cathepsin B or mannose 6-phosphate receptors, and analyze the interactions between cathepsin B and a vacuolar sorting receptor and cathepsin B and putative binding proteins. In the second aim, we will use living colon cancer cells to determine whether: a) cell surface cathepsin B exhibits endopeptidase or exopeptidase activity, and b) cathepsin B is responsible for degradation of extracellular matrix proteins in a novel quenched-fluorescent protein assay. In the third aim, we will manipulate colon cancer model systems to downregulate cathepsin B expression, reduce its cell surface localization or inhibit its activity in order to determine whether cathepsin B is casually linked to colon cancer progression.
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