Center Regional Of Lutte Contre Le Cancer Crlc Val Daurelle Paul Lamarque

Montpellier, France

Center Regional Of Lutte Contre Le Cancer Crlc Val Daurelle Paul Lamarque

Montpellier, France
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Berthier A.,University of Lille Nord de France | Berthier A.,French Institute of Health and Medical Research | Berthier A.,University Droit Et Sante Of Lille | Berthier A.,Institute Pasteur Of Lille | And 26 more authors.
Toxicological Sciences | Year: 2012

The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR twocomponent signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin Awas as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig's blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Laurent-Matha V.,French Institute of Health and Medical Research | Laurent-Matha V.,Center Regional Of Lutte Contre Le Cancer Crlc Val Daurelle Paul Lamarque | Huesgen P.F.,University of British Columbia | Masson O.,French Institute of Health and Medical Research | And 17 more authors.
FASEB Journal | Year: 2012

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. © FASEB.

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