Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.
The lysosomal aspartic protease cathepsin D (cath-D) is over-expressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Cath-D over-expression stimulates tumorigenicity and metastasis. Indeed it plays an essential role in the multiple steps of tumor progression, in stimulating cancer cell proliferation, fibroblast outgrowth and angiogenesis, as well as in inhibiting tumor apoptosis. A mutated cath-D devoid of catalytic activity still proved mitogenic for cancer, endothelial and fibroblastic cells, suggesting an extra-cellular mode of action of cath-D involving a triggering, either directly or indirectly, of an as yet unidentified cell surface receptor. Cath-D is also a key mediator of induced-apoptosis and its proteolytic activity has been involved generally in this event. During apoptosis, mature lysosomal cath-D is translocated to the cytosol. Since cath-D is one of the lysosomal enzymes which requires a more acidic pH to be proteolytically-active relative to the cysteine lysosomal enzymes, such as cath-B and -L, it is open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. This review summarises our current knowledge on cath-D action in cancer progression and metastasis, as well as its dual function in apoptosis.
Liaudet-Coopman
Emmanuelle
E
INSERM U540 'Endocrinologie Moléculaire et Cellulaire des Cancers', Université de Montpellier 1, 60 rue de Navacelles, 34090 Montpellier, France. liaudet@montp.inserm.fr
Beaujouin
Mélanie
M
Derocq
Danielle
D
Garcia
Marcel
M
Glondu-Lassis
Murielle
M
Laurent-Matha
Valérie
V
Prébois
Christine
C
Rochefort
Henri
H
Vignon
Françoise
F
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology*; D009389:Neovascularization, Pathologic; D010447:Peptide Hydrolases / Q000737:chemistry*; D011379:Prognosis
D010447:Peptide Hydrolases; D002402:Cathepsin D