Global cellular response to chemotherapy-induced apoptosis.
Global cellular response to chemotherapy-induced apoptosis.
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DOI：
10.7554/elife.01236
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发表时间：
2013-10-29
期刊：
影响因子：
7.7
通讯作者：
Wells JA
中科院分区：
文献类型：
--
作者：
Wiita AP;Ziv E;Wiita PJ;Urisman A;Julien O;Burlingame AL;Weissman JS;Wells JA
癌细胞在屈服于凋亡之前如何在全球范围内与化疗损伤作斗争在很大程度上是未知的。在这里，我们使用转录，翻译和蛋白水解的综合系统水平的检查，以了解这些事件的癌症治疗的核心。作为一个模型，我们研究骨髓瘤细胞暴露于蛋白酶体抑制剂硼替佐米，一线治疗。尽管有强大的转录变化，无偏见的定量蛋白质组学检测到的背景下，一般的翻译抑制只有少数关键的抗凋亡蛋白的生产。同时核糖体分析进一步揭示了应激反应基因的潜在翻译调控。一旦细胞凋亡机制启动，半胱天冬酶的降解在很大程度上不依赖于上游硼替佐米的作用。此外，以前未表征的非半胱天冬酶蛋白水解事件也参与细胞解构。我们的系统水平数据也支持共靶向抗凋亡调节因子HSF 1，以促进硼替佐米引起的细胞死亡。这种综合方法提供了独特的，深入的了解细胞凋亡的动态，可能证明重要的临床前评估的任何抗癌化合物。DOI：http://dx.doi.org/10.7554/eLife.01236.001许多癌症治疗方法的工作原理是使癌细胞进入一个称为程序性细胞死亡或凋亡的过程的高级阶段。当一个细胞开始凋亡时，它会经历一系列的代谢步骤--比如DNA片段化或体积缩小--最终杀死它。肿瘤中的癌细胞之所以能够生长，是因为它们能够避免凋亡。当癌细胞用细胞毒性药物治疗时，它们不会立即死亡，而是试图避开药物的作用。然而，我们仍然对癌细胞在分子水平上努力避免凋亡所发生的事情知之甚少。现在，Wiita等人结合了研究癌细胞的两种方法--RNA深度测序和定量蛋白质组学--来同时观察多种过程，包括基因转录产生信使RNA（mRNA）分子，这些mRNA分子翻译产生蛋白质，以及细胞接受化疗时这些蛋白质的蛋白水解（或分解）。Wiita等人研究了人类骨髓瘤细胞如何对硼替佐米（一种用于治疗各种血液癌症的药物）做出反应，并发现核糖体-执行翻译步骤的复杂分子机器-通过优先翻译某些mRNA分子来对化疗做出反应，以产生一组保护细胞的蛋白质。开发抑制这些应激反应蛋白的药物可以使癌细胞对现有抗癌药物更敏感。当这种维持生命的努力最终不成功时，蛋白质的破坏似乎与先前保护细胞的尝试无关。通过进一步的工作，Wiita等人开发的“整体细胞反应”方法可能会发现新的药物靶点，提高我们对化疗耐药性的理解，并提供新的方法来监测患者对治疗的反应。DOI：http://dx.doi.org/10.7554/eLife.01236.002网站
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 Many cancer treatments work by causing cancer cells to enter an advanced stage of a process known as programmed cell death or apoptosis. When a cell begins apoptosis, it takes a series of metabolic steps–such as fragmenting its DNA or reducing its volume–that eventually kills it. The cancer cells in tumours are able to grow because they are able to avoid apoptosis. When cancer cells are treated with cytotoxic drugs they do not die immediately but try to stave off the effect of the drug. However, we still know relatively little about what happens at the molecular levels as cancer cells struggle to avoid apoptosis. Now Wiita et al. have combined two methods for studying cancer cells–deep sequencing of RNA and quantitative proteomics–to simultaneously observe a variety of processes, including the transcription of genes to produce messenger RNA (mRNA) molecules, the translation of these mRNA molecules to produce proteins, and the proteolysis (or breakdown) of these proteins when the cells were subjected to chemotherapy. Wiita et al. studied how human myeloma cells responded to bortezomib, a drug that is used to treat various blood cancers, and found that ribosomes–the complex molecular machines that perform the translation step– reacted to the chemotherapy by preferentially translating certain mRNA molecules in order to produce a set of proteins that protect the cell. Developing drugs to inhibit the effects of these stress-response proteins could make the cancer cells more responsive to existing anticancer drugs. When this effort to stay alive is ultimately unsuccessful, the destruction of proteins appears surprisingly unrelated to the previous attempts that were made to protect the cell. With further work the “global cellular response” approach developed by Wiita et al. could lead to the discovery of new drug targets, improve our understanding of drug resistance in chemotherapy, and provide new ways to monitor how patients respond to treatment. DOI: http://dx.doi.org/10.7554/eLife.01236.002