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

Valérie Laurent-Matha, Pitter F Huesgen, Olivier Masson, Danielle Derocq, Christine Prébois, Magali Gary-Bobo, Fabien Lecaille, Bertrand Rebière, Guillaume Meurice, Cédric Oréar, Robert E Hollingsworth, Magnus Abrahamson, Gilles Lalmanach, Christopher M Overall, Emmanuelle Liaudet-Coopman
FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 2012, 26 (12): 5172-81
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.

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