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.
Highlights
Most cytotoxic chemotherapeutics eliminate tumor cells by activating the intrinsic apoptotic pathway (Kaufmann and Earnshaw, 2000)
Similar to previous studies (Shimbo et al, 2012), caspase activity was first detected at 6 hr and the majority of cells were non-viable by 12 hr (Figure 1B). messenger RNA (mRNA) levels were markedly decreased prior to loss of cell viability, as previously seen across a range of apoptotic conditions (Del Prete et al, 2002; Bushell et al, 2004)
We present a systems-level study of how malignant cells respond to apoptosis induced by a clinically relevant chemotherapeutic
Summary
Most cytotoxic chemotherapeutics eliminate tumor cells by activating the intrinsic apoptotic pathway (Kaufmann and Earnshaw, 2000). The final stages leading to mitochondrial pore formation and caspase activation have been well-described at the molecular level (Gonzalvez and Ashkenazi, 2010; Spencer and Sorger, 2011; Parrish et al, 2013). Prior to these terminal stages of apoptosis, it is becoming clear that cells fight to resist the pharmacological insult in ways that appear unique to the treatment applied (Geva-Zatorsky et al, 2010). Recent work has identified hundreds of caspase cleavage substrates in apoptotic cells treated with chemotherapeutics (Shimbo et al, 2012)
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