Pathophysiological functions of cathepsin D: Targeting its catalytic activity versus its protein binding activity?

Abstract

The lysosomal aspartic protease cathepsin D (cath-D) is overexpressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer as it is correlated with the incidence of clinical metastasis. In normal cells, cath-D is localized in intracellular vesicles (lysosomes and endosomes). In cancer cells, overexpressed cath-D accumulates in cells, where it may affect their degradative capacities, and the pro-enzyme is hyper-secreted in the tumor micro-environment. In addition, during apoptosis, lysosomal cath-D is released into the cytosol, where it may interact with and/or cleave pro-apoptotic, anti-apoptotic, or nuclear proteins. Several studies have shown that cath-D affects various different steps in tumor progression and metastasis. Cath-D stimulates cancer cell growth in an autocrine manner, and also cath-D plays a crucial paracrine role in the tumor micro-environment by stimulating fibroblast outgrowth and tumor angiogenesis. A mutant D231N-cath-D, which is devoid of catalytic activity, remained mitogenic, indicating an additional action of cath-D by protein-protein interaction. Targeting cath-D in cancer may require the use of inhibitors of its catalytic activity, but also the development of new tools to inhibit its protein binding functions. Thus, elucidation of the mechanism of action of cath-D is crucial if an appropriate strategy is to be developed to target this protease in cancer. The discovery of new physiological substrates of cath-D using proteomic approaches can be expected to generate new critical targets. The aim of this review is to describe the roles of the cath-D protease in cancer progression and metastasis, as well as its function in apoptosis, and to discuss how it can be targeted in cancer by inhibiting its proteolytic activity and/or its binding protein activity.

The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

“…To test whether a protease was responsible for generating the 30-kDa Aven fragment, we treated MCF-7 cells with various protease inhibitors ( Figure 2c). While incubation with the cysteine protease inhibitor E64 22 and the caspase inhibitor z-VAD 23 showed no influence on Aven processing, the serine protease inhibitor aprotinin 24 and the serine and cysteine protease inhibitor pAPMSF 25 CathD is a prominent member of the subfamily of lysosomal aspartic proteases, and its enzymatic function is not restricted solely to the acidic milieu of lysosomes (for a review see Liaudet-Coopman et al 27 and Masson et al 28 ). CathD has been implicated in positive and negative regulation of apoptosis, and its overexpression has been reported to promote tumorigenesis and metastasis of breast cancer (for a review see Masson et al 28 and Garcia et al 29 ).…”

“…It has been reported that CathD is released from lysosomes into the cytosol at the early onset of apoptosis, thereby leading to the mitochondrial release of Cyt c and caspase activation (for a review see Masson et al 28 ). However, it can be envisaged that before activating the prodeath machinery, CathD must first activate anti-apoptotic proteins (e.g., Aven) in the cytosol to delay death and to allow for damage repair.…”

“…However, it can be envisaged that before activating the prodeath machinery, CathD must first activate anti-apoptotic proteins (e.g., Aven) in the cytosol to delay death and to allow for damage repair. In that regard, the overexpression of endogenous CathD typically observed in breast cancer cells 28 may lead to a constant release of CathD into the cytoplasm, thereby resulting in the activation of anti-death molecules such as Aven, and rendering tumor cells resistant to apoptosis. This notion is supported by the increased production of endogenous DN-Aven observed in the breast cancer cell line MCF-7 ( Figure 2b, left lane; endogenous DN-Aven was also detected in longer exposures of Figure 2a blots, in empty vector-transfected cells (data not shown)).…”

Stress and Cell Death in Yeast Induced by Acetic Acid

“…Pro-CatD outside the cells induces proliferation, angiogenesis, invasion and metastasis (Benes et al, 2008). Additionally, it was demonstrated that inhibition of CatD with pepstatin A induces caspase-dependent apoptosis in neuroblastoma cell lines (Kirkegaard & Jäättelä, 2008) and that overexpression of intracellular CatD in mouse xenografs using rat derived cell lines inhibits apoptosis (Masson et al, 2010). It was also reported that CatD downregulation sensitizes neuroblastoma cells to doxorubicininduced apoptosis, while the opposite effect is observed for CatD overexpression (Sagulenko et al, 2008).…”

“…However, CatD can have anti-apoptotic effects in some cellular types and specific contexts. Indeed, it is generally accepted that CatD is overexpressed and plays an important role in cancer cells (Masson et al, 2010). Pro-CatD outside the cells induces proliferation, angiogenesis, invasion and metastasis (Benes et al, 2008).…”