NDLI: Enzymatically active cathepsin D sensitizes breast carcinoma cells to TRAIL

Content Provider	Springer Nature Link
Author	Jancekova, Blanka Ondrouskova, Eva Knopfova, Lucia Smarda, Jan Benes, Petr
Copyright Year	2016
Abstract	Cathepsin D (CD), a ubiquitously expressed lysosomal aspartic protease, is upregulated in human breast carcinoma and many other tumor types. CD has been repeatedly reported to act as key mediator of apoptosis induced by various chemotherapeutics. However, there is still controversy over the role of enzymatic/proteolytic versus protein-protein interaction activities of CD in apoptotic signaling. The elucidation of molecular mechanism responsible for the effect of CD in the chemotherapy-induced cell death is crucial for development of an appropriate strategy to target this protease in cancer treatment. Therefore, the objective of this study was to investigate the molecular mechanism behind the CD-mediated regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. For this purpose, MDA-MB-231 breast carcinoma cells with an increased level of wt CD (CD) or mutant enzymatically inactive CD (ΔCD) were subjected to TRAIL and the frequency of apoptosis was determined. Our results show that CD facilitates the TRAIL-induced apoptosis of MDA-MB-231 breast cancer cells in enzymatic activity-dependent manner. Moreover, the importance of endosomal/lysosomal acidification in this process was documented. Analysis of the potential substrates specifically cleaved by CD during the TRAIL-induced apoptosis confirmed caspase-8 and Bid proteins as the CD targets. Moreover, in search for protein regulators of apoptosis that can be cleaved by CD at physiologically relevant pH, we identified the Bcl-2 protein as a suitable candidate. The modulatory role of CD in cell response to TRAIL was also confirmed in another breast cancer cell line SKBR3. These experiments identified the CD enzymatic activity as a new factor affecting sensitivity of breast cancer cells to TRAIL.
Starting Page	10685
Ending Page	10696
Page Count	12
File Format	PDF
ISSN	10104283
Journal	Tumor Biology
Volume Number	37
Issue Number	8
e-ISSN	14230380
Language	English
Publisher	Springer Netherlands
Publisher Date	2016-02-11
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Apoptosis Bcl-2 Breast cancer Caspases Cathepsin D TRAIL Cancer Research
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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