Autophagy protects against dasatinib-induced hepatotoxicity via p38 signaling.
Autophagy protects against dasatinib-induced hepatotoxicity via p38 signaling.
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自噬通过 p38 信号传导防止达沙替尼诱导的肝毒性
DOI：
10.18632/oncotarget.3357
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发表时间：
2015-03-20
期刊：
影响因子：
--
通讯作者：
Yang B
中科院分区：
文献类型：
--
作者：
Yang X;Wang J;Dai J;Shao J;Ma J;Chen C;Ma S;He Q;Luo P;Yang B
肝功能障碍是与达沙替尼治疗相关的一种常见副作用，其机制尚不清楚。自噬被认为是肝功能障碍的一个有效的生存或死亡因素，这可能为干预达沙替尼引起的肝毒性提供新的策略。在这项研究中，我们首次证明了自噬的诱导，这与肝损伤的形成是一致的。自噬抑制加剧了达沙替尼诱导的肝功能衰竭，表明自噬是促进生存的一种自卫机制。氧化应激已被证明是自噬和肝脏毒性的重要刺激因素。有趣的是，达沙替尼增加了p38的活性，p38是与肝损伤和自噬相关的氧化应激的关键调节器。P38沉默显著阻断达沙替尼诱导的Lc3-II和p62的降低，并伴随caspase-3和PARP裂解的增加，提示自噬通过p38信号通路减轻了达沙替尼诱导的肝毒性。最后，p38激动剂盐酸异丙肾上腺素(ISO)通过增强自噬而不影响达沙替尼的抗癌活性来减轻达沙替尼诱导的肝功能衰竭。因此，这项研究揭示了p38激活的自噬促进了肝损伤期间的存活率，这可能为达沙替尼的临床应用提供新的方法。
Liver dysfunction is a common side effect associated with the treatment of dasatinib and its mechanism is poorly understood. Autophagy has been thought to be a potent survival or death factor for liver dysfunction, which may shed the light on a novel strategy for the intervention of hepatotoxicity caused by dasatinib. In this study, we show for the first time that autophagy is induced, which is consistent with the formation of liver damage. Autophagy inhibition exacerbated dasatinib-induced liver failure, suggesting that autophagy acted as a self-defense mechanism to promote survival. Oxidative stress has been shown to be an important stimulus for autophagy and hepatotoxicity. Interestingly, dasatinib increased the activity of p38, which is a critical modulator of the oxidative stress related to liver injury and autophagy. p38 silencing significantly blocked LC3-II induction and p62 reduction by dasatinib, which was accompanied by increased caspase-3 and PARP cleavage, indicating that autophagy alleviated dasatinib-induced hepatotoxicity via p38 signaling. Finally, the p38 agonist isoproterenol hydrochloride (ISO) alleviated dasatinib-induced liver failure by enhancing autophagy without affecting the anticancer activity of dasatinib. Thus, this study revealed that p38-activated autophagy promoted survival during liver injury, which may provide novel approaches for managing the clinical applications of dasatinib.
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