Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment
(2012) In FASEB Journal 26(12). p.5172-5181- Abstract
- The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably... (More)
- The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably transfected with human cathepsin D. Cathepsin D extensively cleaved cystatin C in vitro at low pH. Cathepsin D secreted by breast cancer cells also processed cystatin C at the pericellular pH of tumors and so enhancing extracellular proteolytic activity of cysteine cathepsins. Thus, tumor derived cathepsin D assists breast cancer progression by reducing cystatin C activity, which, in turn, enhances cysteine cathepsin proteolytic activity, revealing a new link between protease classes in the protease web.-Laurent-Matha, V., Huesgen, P. F., Masson, O., Derocq, D., Prebois, C., Gary-Bobo, M., Lecaille, F., Rebiere, B., Meurice, G., Orear, C., Hollingsworth, R. E., Abrahamson, M., Lalmanach, G., Overall, C. M., Liaudet-Coopman, E. Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment. FASEB J. 26, 5172-5181 (2012). www.fasebj.org (Less)
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https://lup.lub.lu.se/record/3372683
- author
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cancer, protease web
- in
- FASEB Journal
- volume
- 26
- issue
- 12
- pages
- 5172 - 5181
- publisher
- Wiley
- external identifiers
-
- wos:000311838300037
- scopus:84870332620
- pmid:22898924
- ISSN
- 1530-6860
- DOI
- 10.1096/fj.12-205229
- language
- English
- LU publication?
- yes
- id
- 63e52ee3-6350-4e67-a2f7-66231c4c491e (old id 3372683)
- date added to LUP
- 2016-04-01 13:03:34
- date last changed
- 2023-09-02 18:13:42
@article{63e52ee3-6350-4e67-a2f7-66231c4c491e, abstract = {{The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably transfected with human cathepsin D. Cathepsin D extensively cleaved cystatin C in vitro at low pH. Cathepsin D secreted by breast cancer cells also processed cystatin C at the pericellular pH of tumors and so enhancing extracellular proteolytic activity of cysteine cathepsins. Thus, tumor derived cathepsin D assists breast cancer progression by reducing cystatin C activity, which, in turn, enhances cysteine cathepsin proteolytic activity, revealing a new link between protease classes in the protease web.-Laurent-Matha, V., Huesgen, P. F., Masson, O., Derocq, D., Prebois, C., Gary-Bobo, M., Lecaille, F., Rebiere, B., Meurice, G., Orear, C., Hollingsworth, R. E., Abrahamson, M., Lalmanach, G., Overall, C. M., Liaudet-Coopman, E. Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment. FASEB J. 26, 5172-5181 (2012). www.fasebj.org}}, author = {{Laurent-Matha, Valerie and Huesgen, Pitter F. and Masson, Olivier and Derocq, Danielle and Prebois, Christine and Gary-Bobo, Magali and Lecaille, Fabien and Rebiere, Bertrand and Meurice, Guillaume and Orear, Cedric and Hollingsworth, Robert E. and Abrahamson, Magnus and Lalmanach, Gilles and Overall, Christopher M. and Liaudet-Coopman, Emmanuelle}}, issn = {{1530-6860}}, keywords = {{cancer; protease web}}, language = {{eng}}, number = {{12}}, pages = {{5172--5181}}, publisher = {{Wiley}}, series = {{FASEB Journal}}, title = {{Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment}}, url = {{http://dx.doi.org/10.1096/fj.12-205229}}, doi = {{10.1096/fj.12-205229}}, volume = {{26}}, year = {{2012}}, }