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 tumorinfiltrating 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. [Cancer Res 2007;67(22):10869-78]

No abstract

Cathepsin E is an intracellular aspartic proteinase of the pepsin superfamily, which is predominantly expressed in certain cell types, including the immune system cells and rapidly regenerating gastric mucosal and epidermal keratinocytes. The intracellular localization of this protein varies with different cell types. The endosomal localization is primarily found in antigen-presenting cells and gastric cells. The membrane association is observed with certain cell types such as erythrocytes, osteoclasts, gastric parietal cells and renal proximal tubule cells. This enzyme is also found in the endoplasmic reticulum, Golgi complex and cytosolic compartments in various cell types. In addition to its intracellular localization, cathepsin E occurs in the culture medium of activated phagocytes and cancer cells as the catalytically active enzyme. Its strategic expression and localization thus suggests the association of this enzyme with specific biological functions of the individual cell types. Recent genetic and pharmacological studies have particularly suggested that cathepsin E plays an important role in host defense against cancer cells and invading microorganisms. This review focuses emerging roles of cathepsin E in immune system cells and skin keratinocytes, and in host defense against cancer cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

Cathepsin E (CE) is an intracellular aspartic proteinase implicated in various physiological and pathological processes, yet its actual roles in vivo remain elusive. To assess the physiological significance of CE expression in tumor cells, human CE was stably expressed in human prostate carcinoma ALVA101 cells expressing very little CE activity. Tumor growth in nude mice with xenografted ALVA101/hCE cells was slower than with control ALVA101/mock cells. Angiogenesis antibody array and ELISA assay showed that this was partly due to the increased expression of some antiangiogenic molecules including interleukin 12 and endostatin in tumors induced by CE expression. In vitro studies also demonstrated that, among the cathepsins tested, CE most efficiently generated endostatin from the non-collagenous fragment of human collagen XVIII at mild acidic pH. Histological examination revealed that tumors formed by ALVA101/hCE cells were partitioned by well-developed membranous structures and covered with thickened, well-stratified hypodermal tissues. In addition, both the number and extent of activation of tumor-infiltrating macrophages were more profound in ALVA101/hCE compared to ALVA101/mock tumors. The chemotactic response of macrophages to ALVA101/hCE cells was also higher than that to ALVA/mock cells. These results thus indicate that CE expression in tumor cells induces tumor growth arrest via inhibition of angiogenesis and enhanced immune responses.

The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Growing evidence indicates that these 2 types of gingipains synergistically contribute to the entire virulence of the organism and increase the risk of periodontal disease (PD) by disrupting the host immune system and degrading the host tissue and plasma proteins. Therefore, a dual inhibitor of both gingipains would have attractive clinical potential for PD therapy. In this study, a novel, potent, dual inhibitor of Rgp and Kgp was developed through structure-based drug design, and its biological potency was evaluated in vitro and in vivo. This inhibitor had low nanomolar inhibitory potency (Ki=40 nM for Rgp, Ki=0.27 nM for Kgp) and good selectivity for host proteases and exhibited potent antibacterial activity against P. gingivalis by abrogating its manifold pathophysiological functions. The therapeutic potential of this inhibitor in vivo was also verified by suppressing the vascular permeability that was enhanced in guinea pigs by the organism and the gingival inflammation in beagle dog PD models. These findings suggest that a dual inhibitor of Rgp and Kgp would exhibit noteworthy anti-inflammatory activity in the treatment of PD.