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TRAIL-induced lysosomal cell death pathway in breast carcinoma cells is upregulated by Cathepsin D

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JANČEKOVÁ Blanka BENEŠ Petr KNOPFOVÁ Lucia ONDROUŠKOVÁ Eva ŠMARDA Jan

Rok publikování 2013
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Popis Defects in the classical caspase-dependent apoptosis pathway are often observed in tumor cells. Permeabilization of the lysosomal membrane and leakage of lysosomal cathepsins into cytosol seem to be an effective tool to kill the apoptosis-resistant cancer cells. Lysosomal aspartyl protease cathepsin D (CTSD) is overexpressed in a range of cancer cell types and acts as mediator of apoptosis induced by various chemotherapeutics. TNF-related apoptosis inducing ligand (TRAIL) triggers extrinsic apoptotic pathway by binding to the membrane death receptors. At the same time it can induce lysosomal membrane permeabilization and lysosomal apoptosis-like cell death pathway. In this study we investigated the role of CTSD in the TRAIL-induced apoptosis. MDA-MB-231 breast carcinoma cells were transfected with cDNA coding for CTSDwt and its enzymatically inactive counterpart (CTSDmut). We showed that overexpressed CTSD sensitizes MDA-MB-231 breast carcinoma cells to the TRAIL-induced apoptosis in enzymatic activity-dependent manner. The apoptosis was evaluated by nuclear fragmentation, phosphatidylserine externalization and caspase activation. The CTSD-mediated pro-apoptotic effect was partially reversed by both CTSD inhibitor and caspase 8 inhibitor. We also showed that increased frequency of apoptosis of cells overexpressing CTSD wt corresponded to cleavage of the pro-apoptotic Bid protein, the Bcl-2 family member earlier identified as one of the targets of CTSD in cancer cells, and the anti-apoptotic Bcl-2 protein, which seems to be a novel CTSD target. The TRAIL-induced apoptosis was rapidly diminished by increased intralysosomal pH, confirming the role of lysosomes and lysosomal proteases in the TRAIL-induced apoptotic signaling. We conclude that TRAIL triggers the lysosomal apoptosis-like cell death pathway in breast carcinoma cells and this effect can by upregulated by CTSD in enzymatic activity-dependent manner. Hence identification of novel potential substrates of CTSD is required to elucidate its role in pro-apoptotic signaling.
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