Pathophysiological functions of cathepsin D: Targeting its catalytic activity versus its protein binding activity?
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.
Masson
Olivier
O
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.
Bach
Anne-Sophie
AS
Derocq
Danielle
D
Prébois
Christine
C
Laurent-Matha
Valérie
V
Pattingre
Sophie
S
Liaudet-Coopman
Emmanuelle
E
D000818:Animals; D017209:Apoptosis; D055162:Biocatalysis / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects
D002402:Cathepsin D