Publication details
Cleavage of Bcl-2 by cathepsin D: a novel mechanism of cathepsin D-mediated regulation of apoptosis
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| Year of publication | 2014 |
| Type | Conference abstract |
| Citation | |
| Description | Cathepsin D (CTSD) is a member of the subfamily of lysosomal aspartic proteases. However, its enzymatic function is not restricted solely to the acidic milieu of lysosomes. It can facilitate cancer cell migration and invasion by digesting the basement membrane, extracellular matrix, and connective tissue. Because of its mitogenic and proteolytic activities, CTSD has been suggested to act as prognostic marker in many tumour types, especially breast cancer. CTSD has been also implicated in positive and negative regulation of apoptosis. In this study we investigated the role of CTSD in the TRAIL-induced apoptotic signaling. TRAIL (Tumor necrosis factor -related apoptosis-inducing ligand) induces extrinsic apoptotic pathway by binding to its plasma membrane death receptors. Interestingly, TRAIL induces apoptosis preferentially in various types of tumor cells without significant toxicity towards normal tissue. MDA-MB-231 breast carcinoma cells were transfected with cDNA coding for CTSDwt and its enzymatically inactive counterpart (CTSDmut). Control and CTSDwt/CTSDmut overexpressing stable transfectants were then exposed to TRAIL and frequency of apoptosis was determined by nuclear fragmentation, PARP cleavage and activation of caspases. In this study we describe that CTSD facilitates the TRAIL-induced apoptosis of breast cancer MDA-MB-231 cells in enzymatic activity-dependent manner. Analysis of the potential substrates specifically cleaved by CTSD during apoptotic cell death progression provided a new evidence of the CTSD-mediated cleavage of the Bcl-2 protein. The Bcl-2 cleavage occurred both in MDA-MB-231 cells and in vitro in a range of pH values as detected by immunoblotting. As Bcl-2 is prominent anti-apoptotic regulator, its cleavage may represent novel mechanism of cathepsin D-mediated regulation of apoptosis. |
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