title: Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface.
abstract: 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.
authors.affiliation: Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kawakubo
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Iwata
authors.forename: Masashi
authors.initials: M
authors.lastname: Shin
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasukochi
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism; D020059:Cathepsin E / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D020059:Cathepsin E