Cathepsin D Overexpressed by Cancer Cells Can Enhance Apoptosis-dependent Chemo-sensitivity Independently of Its Catalytic Activity

  • Melanie Beaujouin
  • Emmanuelle Liaudet-Coopman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)


The aspartic protease cathepsin D (CD) is a key mediator of inducedapoptosis and its proteolytic activity has been generally involved in this event. During apoptosis, CD is translocated to the cytosol. Since CD is one of the lysosomal enzymes that requires a more acidic pH to be proteolytically-active relative to the cysteine lysosomal enzymes such as cathepsin-B and cathepsin-L, it is therefore open to question whether cytosolic CD might be able to cleave substrate(s) implicated in the apoptotic cascade. Here, we have investigated the role of (wild-type) wt CD and its proteolytically inactive counterpart overexpressed by 3Y1-Adl2 cancer cells during chemotherapeutic-induced cytotoxicity and apoptosis, as well as the relevance of CD catalytic function. We demonstrate that wt or mutated catalytically inactive CD strongly enhances chemo-sensitivity and apoptotic response to etoposide. Both wt and mutated inactive CD are translocated to the cytosol, increasing the release of cytochrome c, the activation of caspases-9 and caspases-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 CD on cell death is independent of its catalytic activity. Overall, our results imply that cytosolic CD stimulates apoptotic pathways by interacting with a member of the apoptotic machinery rather than by cleaving specific substrate(s).


Lysosomal Enzyme Aspartic Protease Cell Death Differ Etoposide Treatment Aspartic Protease Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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© Springer 2008

Authors and Affiliations

  • Melanie Beaujouin
  • Emmanuelle Liaudet-Coopman
    • 1
  1. 1.Inserm Unit 540MontpellierFrance

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