title: Global cellular response to chemotherapy-induced apoptosis.
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.
authors.affiliation: Department 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.
authors.forename: Arun P
authors.initials: AP
authors.lastname: Wiita
authors.forename: Etay
authors.initials: E
authors.lastname: Ziv
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wiita
authors.forename: Anatoly
authors.initials: A
authors.lastname: Urisman
authors.forename: Olivier
authors.initials: O
authors.lastname: Julien
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D000076249:Heat Shock Transcription Factors; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis; D059748:Proteolysis; D011719:Pyrazines / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D011480:Protease Inhibitors; D011719:Pyrazines; D014157:Transcription Factors; D000069286:Bortezomib; D020169:Caspases
keywords: Human; apoptosis; caspase; myeloma; proteomics; ribosome profiling