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Elife. 2013 Oct 29;2:e01236. doi: 10.7554/eLife.01236.

Global cellular response to chemotherapy-induced apoptosis.

Author information

  • 1Department of Pharmaceutical Chemistry , University of California, San Francisco , San Francisco , United States ; Department of Laboratory Medicine , University of California, San Francisco , San Francisco , United States.

Erratum in

  • Elife. 2013;2:e01816.

Abstract

How cancer cells globally struggle with a chemotherapeutic insult before succumbing to apoptosis is largely unknown. Here we use an integrated systems-level examination of transcription, translation, and proteolysis to understand these events central to cancer treatment. As a model we study myeloma cells exposed to the proteasome inhibitor bortezomib, a first-line therapy. Despite robust transcriptional changes, unbiased quantitative proteomics detects production of only a few critical anti-apoptotic proteins against a background of general translation inhibition. Simultaneous ribosome profiling further reveals potential translational regulation of stress response genes. Once the apoptotic machinery is engaged, degradation by caspases is largely independent of upstream bortezomib effects. Moreover, previously uncharacterized non-caspase proteolytic events also participate in cellular deconstruction. Our systems-level data also support co-targeting the anti-apoptotic regulator HSF1 to promote cell death by bortezomib. This integrated approach offers unique, in-depth insight into apoptotic dynamics that may prove important to preclinical evaluation of any anti-cancer compound. DOI:http://dx.doi.org/10.7554/eLife.01236.001.

KEYWORDS:

Human; apoptosis; caspase; myeloma; proteomics; ribosome profiling

Comment in

PMID:
24171104
PMCID:
PMC3808542
DOI:
10.7554/eLife.01236
[PubMed - indexed for MEDLINE]
Free PMC Article
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