Cancer Letters

Cancer Letters

Volume 237, Issue 2, 18 June 2006, Pages 167-179
Cancer Letters

Mini-review
Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis

https://doi.org/10.1016/j.canlet.2005.06.007Get rights and content

Abstract

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.

Introduction

Proteases of the cathepsin family are among the most studied lysosomal hydrolases that degrade proteins in lysosomes at an acidic pH. Cathepsins can be divided into three subgroups according to their active-site amino acid (i.e., cysteine (B, C, H, F, K, L, O, S, V, W), aspartic (D and E) or serine (G) cathepsins) [1].

Apart from their function in general protein turnover, knock-out experiments have revealed that cathepsins can also perform specific functions, such as neovascularization of endothelial progenitor cells [2], antigen presentation [3], cell growth and tissue homeostasis [4], [5], [6], [7]. Interestingly, cathepsins also have crucial functions outside the lysosomal compartment (i.e., degradation of the extracellular matrix or induction of fibroblast invasive growth when secreted into the extracellular space and execution of programmed cell death when released into the cytosol [8], [9], [10]).

Several members of the cathepsins, in particular the aspartic protease cathepsin D (cath-D) and the cysteine proteases cathepsin B and L, have been implicated in cancer progression and metastasis [8], [11], [12], [13]. More recently, these cathepsins were shown to mediate the lysosomal cell death pathways [10].

The aim of the present review is to discuss the role of cath-D in cancer progression and metastasis, as well as its dual function in apoptosis.

Section snippets

Cath-D: basic information

Cath-D [E.C. 3.4.23.5] is an aspartic endo-protease that is ubiquitously distributed in lysosomes [14]. It was considered for a long time that the main function of cath-D was to degrade proteins in lysosomes at an acidic pH. In addition to its classical role as a major protein-degrading enzyme in lysosomes and phagosomes, it has been shown that cath-D can also activate precursors of biologically active proteins in pre-lysosomal compartments of specialized cells [15].

Knock-out experiments of

Maturation of cath-D

Mechanisms associated with the processing and activation of lysosomal proteases remain largely unknown [21]. In general, three types of mechanism have been reported on for the processing and activation of aspartic proteases. The first, complete auto-activation, has been described for porcine pepsinogen [22]. The second is represented by fully-assisted activation of pro-renin [23]. Whilst the third proposed for cath-D is a combination of partial auto-activation and enzyme-assisted activation

Over-expression of cath-D in breast cancer cells

Studies in estrogen receptor positive breast cancer cell lines revealed that this housekeeping enzyme is highly regulated by estrogens and certain growth factors (i.e. IGF1, EGF) [46], [47]. The mechanism of this over-expression does not seem to involve gene amplification or major chromosomal rearrangements [48]. In ER-positive breast cancer cell lines, both estrogen and growth factors stimulate cath-D protein and mRNA accumulation levels [49], [50]. As far as other steroid responsive genes are

Cath-D as a prognostic factor in breast cancer

Different approaches, such as immuno-histochemistry, in situ hybridization, cytosolic immunoassay and Northern and Western blot analyses have indicated that in most breast cancer tumors, cath-D is over-expressed from 2- to 50-fold compared to its concentration in other cell types such as fibroblasts or normal mammary glands [52]. Several independent clinical studies have shown that the cath-D level in primary breast cancer cytosol is an independent prognostic parameter correlated with the

Cath-D stimulates metastasis

The direct role of cath-D in cancer metastasis was first demonstrated in rat tumor cells in which transfection-induced cath-D over-expression increased their metastatic potential in vivo [65], [66]. In this rat tumor model, the cath-D mechanism responsible for metastasis stimulation seemed to have a positive effect on cell proliferation, favouring the growth of micro-metastases, rather than increasing the invasive potential [65], [66], [67], [68], [69]. Using an RNA antisense strategy we showed

Physiologic and pathologic role of cath-D in apoptosis

The function of cath-D in apoptosis is not yet fully understood and needs further investigation. Cath-D can either prevent apoptosis, as described under physiological conditions with cath-D knock-out mice experiments [4], [5], [6], [7], or can promote apoptosis induced by cytotoxic agents [106], [107], [108], [109], [110], [111], [112], [113], [114]. This duality in the role of cath-D in apoptosis is also highlighted by our apparently conflicting results obtained with transfected 3Y1-Ad12 cell

Conclusion

Cath-D is not only a mitogen for cancer cells but appears to be also a crucial paracrine factor for endothelial and fibroblastic cells. Its action in cancer seems to implicate its extracellular interaction with a cell surface membrane receptor. This receptor has not yet been identified, but it is clearly of considerable potential interest to clarify the mechanisms involved and to consider their medical applications. Cath-D evidently plays a dual role in apoptosis. In such physiological and

Acknowledgements

This review was written in the memories of Dr Françoise Vignon who was a pioneer in cath-D field and largely contributed to the studies on cath-D. This work was supported by University of Montpellier I, Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer (grant 3344), Ligue Nationale contre le Cancer who provided a fellowship for Mélanie Beaujouin, and Ministère de la Culture, de I'Enseignement Supérieur et de la Recherche au Luxembourgwho

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