JAK2/STAT3 Pathway Mediates Protection of Metallothionein Against Doxorubicin-Induced Cytotoxicity in Mouse Cardiomyocytes
JAK2/STAT3 Pathway Mediates Protection of Metallothionein Against Doxorubicin-Induced Cytotoxicity in Mouse Cardiomyocytes
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DOI：
10.1177/1091581815614261
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发表时间：
2016-05-01
影响因子：
2.2
通讯作者：
Peng, Shuangqing
中科院分区：
文献类型：
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作者：
Rong, Jing;Li, Lizhong;Peng, Shuangqing
阿霉素（Dox）是最重要的抗癌药物之一；但其严重的心脏毒性限制了其临床应用。在我们之前的研究中，我们发现在MT-/-心肌细胞和MT+/+心肌细胞中，经Dox处理后，janus激活的激酶/信号传导因子和转录激活因子3 （JAK2/STAT3）通路的基因表达水平是不同的。因此，本研究旨在探讨JAK2/STAT3通路在金属硫蛋白（MT）保护dox诱导的心脏毒性中的作用。Tyrphostin AG490 （-cyano-（3,4-二羟基）- n -benzylcinnamide）是一种合成蛋白酪氨酸激酶抑制剂，最初被认为是一种特异性JAK2抑制剂，可以抑制JAK2/STAT3信号通路。在本研究中，AG490被用于评估JAK2/STAT3在MT对dox诱导的心脏毒性的保护作用。AG490可以通过增加乳酸脱氢酶和凋亡细胞数量来减弱MT的保护作用。有趣的是，通过活性氧生成、脂质过氧化和蛋白质羰基化测量，经AG490预处理的MT-/-心肌细胞比MT+/+对dox诱导的细胞毒性更敏感。Dox上调了金属硫蛋白1和MT-2信使RNA， AG490降低了MT-1和MT-2的蛋白表达。Dox处理后，MT+/+心肌细胞中p-Jak2和p-Stat3蛋白表达水平显著升高，提示JAK2/STAT3途径部分参与MT对Dox诱导的心脏毒性的保护。
Doxorubicin (Dox) is one of the most important anticancer agents; however, its clinical application is limited by its severe cardiotoxicity. In our previous study, we found that the gene expression levels of the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway were different between MT-/- cardiomyocytes and MT+/+ cardiomyocytes when they were treated with Dox. Thus, this study was intended to investigate the role of JAK2/STAT3 pathway in metallothionein (MT) protection of Dox-induced cardiotoxicity. Tyrphostin AG490 (-cyano-(3,4-dihydroxy)-N-benzylcinnamide) is a synthetic protein tyrosine kinase inhibitor which at first has been considered as a specific JAK2 inhibitor and can inhibit the JAK2/STAT3 signaling pathway. In the present study, AG490 was used to assess the role of JAK2/STAT3 in MT protection against Dox-induced cardiotoxicity. The AG490 can attenuate the MT protection by increasing lactate dehydrogenase and the number of apoptotic cells. Interestingly, pretreated with AG490, MT-/- cardiomyocytes were more sensitive than MT+/+ to Dox-induced cytotoxicity as measured by reactive oxygen species generation, lipid peroxidation, and protein carbonylation. Metallothionein 1 and MT-2 messenger RNA were upregulated by Dox, and AG490 decreased the protein expression of MT-1 and MT-2. After Dox treatment, the protein expression of p-Jak2 and p-Stat3 levels was significantly increased in MT+/+ cardiomyocytes, suggesting that the JAK2/STAT3 pathway was partially involved in MT protection against Dox-induced cardiotoxicity.