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

Liaudet-Coopman, Emmanuelle; Beaujouin, Mélanie; Derocq, Danielle; Garcia, Marcel; Glondu-Lassis, Murielle; Laurent‐Matha, Valérie; Prébois, Christine; Rochefort, Henri; Vignon, Françoise

doi:10.1016/j.canlet.2005.06.007

Cited by 302 publications

(230 citation statements)

References 117 publications

(147 reference statements)

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“…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 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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The anti-apoptotic molecule Aven was originally identified in a yeast two-hybrid screen for Bcl-x L -interacting proteins and has also been found to bind Apaf-1, thereby interfering with Apaf-1 self-association during apoptosome assembly. Aven is expressed in a wide variety of adult tissues and cell lines, and there is increasing evidence that its overexpression correlates with tumorigenesis, particularly in acute leukemias. The mechanism by which the anti-apoptotic activity of Aven is regulated remains poorly understood. Here we shed light on this issue by demonstrating that proteolytic removal of an inhibitory N-terminal Aven domain is necessary to activate the anti-apoptotic potential of the molecule. Furthermore, we identify Cathepsin D (CathD) as the protease responsible for Aven cleavage. On the basis of our results, we propose a model of Aven activation by which its N-terminal inhibitory domain is removed by CathD-mediated proteolysis, thereby unleashing its cytoprotective function.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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“…Our profiling reveals that cathepsin D becomes more abundant in the aggressive cell lines. While it functionally stimulates metastasis, it also acts as a mitogen for cancer cells and promotes angiogenesis [63], and induces stromal proliferation in tumors. In turn, the stromal fibroblasts produce proteases that aid in the degradation of the extracellular matrix [64][65][66].…”

Section: Validation Of the Lc-ms Datamentioning

confidence: 99%

Identification of Differentially Secreted Biomarkers Using LC-MS/MS in Isogenic Cell Lines Representing a Progression of Breast Cancer

et al. 2007

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Proteins secreted (the secretome) from cancer cells are potentially useful as biomarkers of the disease. Using LC-MS/MS, the secreted proteomes from a series of isogenic breast cancer cell lines varying in aggressiveness were analyzed by mass spectrometry: non-tumorigenic MCF10A, premalignant/ tumorigenic MCF10AT, tumorigenic/locally invasive MCF10 DCIS.com and tumorigenic/ metastatic MCF 10CA cl. D. Proteomes were obtained from conditioned serum-free media, partially fractionated using a small reverse phase C2 column and digested with trypsin for analysis by LC-MS/MS, using a method previously shown to give highly enriched secreted proteomes (Mbeunkui, et. al., J. Prot. Res. 5, 899-906 2006). The search files produced from 5 analyses (3 separate preparations) were combined for database searching (Mascot) which produced a list of over 250 proteins from each cell line. The aim was to discover highly secreted proteins which changed significantly in abundance corresponding with aggressiveness. The most apparent changes were observed for alpha-1-antichymotrypsin and galectin-3-binding protein which were highly secreted proteins from MCF10 DCIS.com and MCF10CA cl. D, yet undetected in the MCF10A and MCF10AT cell lines. Other proteins showing increasing abundance in the more aggressive cell lines included alpha-1-antitrypsin, cathepsin D and lysyl oxidase. The S100 proteins, often associated with metastasis, showed variable changes in abundance. While the cytosolic proteins were low (e.g. actin and tubulin), there was significant secretion of proteins often associated with the cytoplasm. These proteins were all predicted as products of non-classical secretion (SecretomeIP, Center for Biological Sequence Analysis). The LC-MS/MS results were verified for five selected proteins by western blot analysis, and the relevance of other significant proteins is discussed. Comparisons with two other aggressive breast cancer cell lines are included and the protein with consistent association with aggressiveness in all lines, and in unrelated cancer cells, was the galectin-3-binding protein which has been associated with breast, prostate and colon cancer earlier, supporting the approach and findings. This analysis of an isogenic series of cell lines suggests the potential usefulness of the secretome for identifying prospective markers for the early detection and aggressiveness/progression of cancer.

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“…The lysosomal aspartic protease cathepsin-D (cath-D) is overexpressed and abundantly secreted by human epithelial breast cancer cells Rochefort and Liaudet-Coopman, 1999;Liaudet-Coopman et al, 2006). This overproduction in breast cancer is correlated with a poor prognosis (Ferrandina et al, 1997;Foekens et al, 1999;Rodriguez et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

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The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1b-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231N cath-D, and pro-D231N cath-D all significantly inhibited LRP1 RIP by preventing LRP1b-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

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

Cited by 302 publications

References 117 publications

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

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

Identification of Differentially Secreted Biomarkers Using LC-MS/MS in Isogenic Cell Lines Representing a Progression of Breast Cancer

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

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