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Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment

Laurent-Matha, Valerie; Huesgen, Pitter F.; Masson, Olivier; Derocq, Danielle; Prebois, Christine; Gary-Bobo, Magali; Lecaille, Fabien; Rebiere, Bertrand; Meurice, Guillaume and Orear, Cedric, et al. (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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published
subject
keywords
cancer, protease web
in
FASEB Journal
volume
26
issue
12
pages
5172 - 5181
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • wos:000311838300037
  • scopus:84870332620
ISSN
1530-6860
DOI
10.1096/fj.12-205229
language
English
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yes
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63e52ee3-6350-4e67-a2f7-66231c4c491e (old id 3372683)
date added to LUP
2013-02-01 07:00:15
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2017-10-22 04:00:48
@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},
  keyword      = {cancer,protease web},
  language     = {eng},
  number       = {12},
  pages        = {5172--5181},
  publisher    = {The Federation of American Societies for Experimental Biology},
  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},
  volume       = {26},
  year         = {2012},
}