Journal
ONCOGENE
Volume 27, Issue 33, Pages 4580-4591Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.96
Keywords
protease substrates; caspase-like activity; taxol; cytotoxic granule
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We analysed the involvement of proteases during taxol-mediated cell death of human A549 non-small-cell lung carcinoma cells using a proteomics approach that specifically targets protein N termini and further detects newly formed N termini that are the result of protein processing. Our analysis revealed 27 protease-mediated cleavages, which we divided in sites C-terminal to aspartic acid (Asp) and sites C-terminal to non-Asp residues, as the result of caspase and non-caspase protease activities, respectively. Remarkably, some of the former were insensitive to potent pancaspase inhibitors, and we therefore suggest that previous inhibitor-based studies that report on the caspase-independent nature of taxol-induced cell death should be judged with care. Furthermore, many of the sites C-terminal to non-Asp residues were also uniquely observed in a model of cytotoxic granule-mediated cell death and/or found by in vitro cataloging human mu-calpain substrates using a similar proteomics technique. This thus raises the hypothesis that killing tumor cells by chemotherapy or by immune cells holds similar non-Asp-specific proteolytic components with strong indications to calpain activity.
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