Abstract
The aspartic protease cathepsin D (cath-D) is a key mediator of induced-apoptosis and its proteolytic activity has been generally involved in this event. During apoptosis, cath-D is translocated to the cytosol. Because cath-D is one of the lysosomal enzymes that requires a more acidic pH to be proteolytically active relative to the cysteine lysosomal enzymes such as cath-B and -L, it is therefore open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. Here, we have investigated the role of wild-type cath-D and its proteolytically inactive counterpart overexpressed by 3Y1-Ad12 cancer cells during chemotherapeutic-induced cytotoxicity and apoptosis, as well as the relevance of cath-D catalytic function. We demonstrate that wild-type or mutated catalytically inactive cath-D strongly enhances chemo-sensitivity and apoptotic response to etoposide. Both wild-type and mutated inactive cath-D are translocated to the cytosol, increasing the release of cytochrome c, the activation of caspases-9 and -3 and the induction of a caspase-dependent apoptosis. In addition, pretreatment of cells with the aspartic protease inhibitor, pepstatin A, does not prevent apoptosis. Interestingly therefore, the stimulatory effect of cath-D on cell death is independent of its catalytic activity. Overall, our results imply that cytosolic cath-D stimulates apoptotic pathways by interacting with a member of the apoptotic machinery rather than by cleaving specific substrate(s).
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Acknowledgements
We thank Dr Karin Öllinger (Linköping University, Sweden) for her kind help and valuable discussions concerning the digitonin method, Jean-Yves Cance for the photographs, Nicole Lautredou-Audouy (Centre de Ressources en Imagerie Cellulaire) for confocal microscopy and Nadia Kerdjadj for her secretarial assistance. This work was supported by Institut National de la Santé et de la Recherche Médicale, University of Montpellier I, Association pour la Recherche sur le Cancer (Grant 3344, E Liaudet-Coopman and Grant 3118, S Baghdiguian), Ligue Nationale contre le Cancer who provided a fellowship for Mélanie Beaujouin, and Ministère de la Culture, de l’Enseignement Supérieur et de la Recherche du Luxembourg who provided a fellowship for Dr Murielle Glondu-Lassis.
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Beaujouin, M., Baghdiguian, S., Glondu-Lassis, M. et al. Overexpression of both catalytically active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity. Oncogene 25, 1967–1973 (2006). https://doi.org/10.1038/sj.onc.1209221
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DOI: https://doi.org/10.1038/sj.onc.1209221
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