Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.
Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.
复制标题
化疗药物会减少肌管中的蛋白质合成和核糖体容量，与氧化应激无关。
DOI：
10.1152/ajpcell.00116.2021
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Nader,GustavoA
中科院分区：
文献类型：
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作者：
Guo,Bin;Bennet,Devasier;Belcher,DanielJ;Kim,Hyo-Gun;Nader,GustavoA
化疗药物（CA）是治疗多种癌症的一线药物。尽管它们在阻止肿瘤进展方面有效，但与CA相关的副作用通过不完全理解的机制促进肌肉损失。为了解决这个问题，我们首先确定了氧化应激如何损害C2C12肌管中的蛋白质合成。活性氧（ROS）的瞬时升高导致蛋白质合成缺陷和核糖体（r）RNA水平降低。氧化应激并不降低rRNA基因（rDNA）的转录，但它引起的rRNA和蛋白质氧化的增加。为了确定CA是否独立于氧化应激影响蛋白质合成，我们将肌管暴露于紫杉醇（PTX），阿霉素（DXR）或Marizlavine（Mzb），剂量确实导致ROS水平升高（亚ROS）。暴露于CA降低蛋白质合成和rRNA水平，但与氧化应激不同，亚ROS暴露损害rDNA转录。这些结果表明，虽然氧化应激通过损害核糖体的数量和质量来破坏蛋白质合成，但在亚ROS剂量下的CA至少部分地通过减少rDNA转录来损害蛋白质合成和核糖体能力。因此，CA除了以ROS非依赖性方式直接降低肌管的核糖体能力之外，还通过引起氧化应激对蛋白质合成产生负面影响。
Chemotherapeutic agents (CAs) are first-line antineoplastic treatments against a wide variety of cancers. Despite their effectiveness in halting tumor progression, side effects associated with CAs promote muscle loss by incompletely understood mechanisms. To address this problem, we first identified how oxidative stress impairs protein synthesis in C2C12 myotubes. Transient elevations in reactive oxygen species (ROS) resulted in protein synthesis deficits and reduced ribosomal (r)RNA levels. Oxidative stress did not reduce rRNA gene (rDNA) transcription, but it caused an increase in rRNA and protein oxidation. To determine whether CAs affect protein synthesis independent of oxidative stress, we exposed myotubes to Paclitaxel (PTX), Doxorubicin (DXR), or Marizomib (Mzb) at doses that did result in elevated ROS levels (sub-ROS). Exposure to CAs reduced protein synthesis and rRNA levels, but unlike oxidative stress, sub-ROS exposures impaired rDNA transcription. These results indicate that although oxidative stress disrupts protein synthesis by compromising ribosomal quantity and quality, CAs at sub-ROS doses compromise protein synthesis and ribosomal capacity, at least in part, by reducing rDNA transcription. Therefore, CAs negatively impact protein synthesis by causing oxidative stress in addition to directly reducing the ribosomal capacity of myotubes in a ROS-independent manner.