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首页> 外文期刊>Archives of Toxicology >p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts
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p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts

机译：P66SHC信号传导涉及通过蒽环霉素治疗大鼠心肌细胞引起的应力响应

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摘要

The adaptor protein p66Shc modulates cellular redox status integrating oxidative stress with mitochondrial stress responses. Upon oxidative stress, p66Shc is translocated to mitochondria or mitochondria-associated membranes in a multi-step process, resulting in locally increased reactive oxygen species production. This signaling pathway is believed to be important in the context of drug-induced organ toxicity. The use of anthracyclines as anticancer agents is limited due to a dose-dependent and cumulative toxicity resulting in cardiomyopathy. Treatment with the anthracycline doxorubicin (DOX) results in a dose-dependent and cumulative cardiotoxicity which is mediated, at least in part, by increased oxidative stress. In the present study, we investigated for the first time whether p66Shc signaling is activated during DOX treatment of the rat cardiomyoblast H9c2 cell line. We further tested whether the transcriptional factor FoxO3a, which activates target genes responsible for apoptosis and cell cycle arrest, is also involved in p66Shc-dependent redox signaling pathway. Our results suggest that DOX treatment induces p66Shc protein up-regulation specifically in nuclear fractions. Increased nuclear expression of FoxO3a was also detected in H9c2 cells after DOX treatment. Treatment with the antioxidant and protein kinase C (PKC-beta) inhibitor hispidin decreased DOX-induced activation of caspase 9 and p66Shc alterations. Taking together, we hypothesize that p66Shc signaling is involved in the activation of stress/toxicity responses elicited by the treatment of H9c2 cells with DOX. Hence, the selective inhibition of this redox pathway may be a promising therapeutic approach to circumvent DOX cardiotoxicity.
机译：适配器蛋白P66SHC调节细胞氧化还原状态与线粒体应力反应相结合的氧化应激。在氧化应激后，P66SHC在多步骤过程中旋转到线粒体或线粒体相关膜，导致局部增加的反应性氧物种生产。该信号通路被认为在药物诱导的器官毒性的背景下是重要的。由于具有心肌病的剂量依赖性和累积毒性，蒽环类作为抗癌剂的使用受到限制。用蒽环素多柔比星（DOX）的处理导致剂量依赖性和累积的心脏毒性，其至少部分地通过增加氧化应激介导。在本研究中，我们首次研究了在大鼠心肌细胞H9C2细胞系的DOX处理期间是否激活P66SHC信号传导。我们进一步测试了转录因子FoxO3a，其激活负责细胞凋亡和细胞周期停滞的靶基因，也参与P66SHC依赖于氧化还原信号通路。我们的研究结果表明，Dox治疗诱导核级分的P66SHC蛋白质上调。在DOX治疗后，在H9C2细胞中也检测到FOXO3A的核表达增加。用抗氧化剂和蛋白激酶C（PKC-Beta）抑制剂Hispidin治疗减少了Dox诱导的Caspase 9和P66SHC改变的活化。在一起，我们假设P66SHC信号传导参与通过用DOX治疗H9C2细胞引发的应激/毒性反应的激活。因此，对该氧化还原途径的选择性抑制可能是旨在规避Dox心脏毒性的有希望的治疗方法。

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