Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface

The aspartic proteinase Cathepsin E is expressed predominantly in cells of the immune system and highly secreted by activated phagocytes, and deficiency of Cathepsin E in mice results in a phenotype affecting immune responses. However, because physiologic substrates for Cathepsin E have not yet been identified, the relevance of these observations to the physiologic functions of this protein remains speculative. Here, we show that Cathepsin E specifically induces growth arrest and Apoptosis in human prostate carcinoma tumor cell lines without affecting normal cells by catalyzing the proteolytic release of soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from the cell surface. The antitumor activity of Cathepsin E was corroborated by in vivo studies with mice bearing human and mouse tumor transplants. Administration of purified Cathepsin E into human tumor xenografts in nude mice dose-dependently induced Apoptosis in the tumor cells to inhibit tumor growth. The growth, viability, and metastasis of mouse B16 melanoma cells were also more profound in Cathepsin E-deficient mice compared with those in the syngeneic wild-type and transgenic mice overexpressing Cathepsin E. Taken together, the number of apoptotic tumor cells, as well as tumor-infiltrating activated macrophages, was apparently reduced in Cathepsin E-deficient mice compared with those in the Other two groups, implying the positive correlation of endogenous Cathepsin E levels with the extent of tumor suppression in vivo. These results thus indicate that Cathepsin E plays a substantial role in host defense against tumor cells through TRAIL-dependent Apoptosis and/or tumor-associated macrophage-mediated cytotoxicity.