Cathepsin E Prevents Tumor Growth and Metastasis by Catalyzing the Proteolytic Release of Soluble TRAIL from Tumor Cell Surface

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 22; pp. 10869 - 10878
• Main Authors: KAWAKUBO, Tomoyo, OKAMOTO, Kuniaki, IWATA, Jun-Ichi, SHIN, Masashi, OKAMOTO, Yoshiko, YASUKOCHI, Atsushi, NAKAYAMA, Keiichi I, KADOWAKI, Tomoko, TSUKUBA, Takayuki, YAMAMOTO, Kenji
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2007
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Carcinoma - metabolism; Cathepsin E - metabolism; Cell Membrane - metabolism; Humans; Immune System; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neoplasm Metastasis; Neoplasms - metabolism; Pharmacology. Drug treatments; Prostatic Neoplasms - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumors; Enzyme; Cathepsin E; Cytokine; Soluble form; Metastasis; Malignant tumor; Cell surface; Prevention; Peptidases; Tumor growth; Tumor necrosis factor; Hydrolases; TNF related apoptosis inducing ligand; Aspartic endopeptidases; Tumor cell; Cancer
• DOI: 10.1158/0008-5472.can-07-2048
• ISSN: 0008-5472

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.