Epoxyeicosatrienoic Acids Attenuate Reactive Oxygen Species Level, Mitochondrial Dysfunction, Caspase Activation, and Apoptosis in Carcinoma Cells Treated with Arsenic Trioxide
Epoxyeicosatrienoic Acids Attenuate Reactive Oxygen Species Level, Mitochondrial Dysfunction, Caspase Activation, and Apoptosis in Carcinoma Cells Treated with Arsenic Trioxide
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DOI：
10.1124/jpet.111.180505
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发表时间：
2011-11-01
影响因子：
3.5
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Liu, Liu;Chen, Chen;Wang, Dao Wen
环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，EAE）和细胞色素P450表氧化酶CYP 2 J2通过直接刺激肿瘤细胞生长和抑制肿瘤细胞凋亡在体内和体外促进肿瘤发生。在此，我们描述了一种新的机制，抑制肿瘤细胞凋亡的Eclase。在Tca-8113癌细胞中，抗白血病药物三氧化二砷（ATO）导致活性氧（ROS）的产生，损害线粒体功能，并诱导凋亡。11，12-EET预处理增加抗氧化酶超氧化物歧化酶和过氧化氢酶的表达，抑制ATO诱导的细胞凋亡。11，12-EET也阻止ATO诱导的p38丝裂原活化蛋白激酶、c-Jun NH（2）-末端激酶、caspase-3和caspase-9的活化。因此，11，12-EET预处理减弱了ATO处理后观察到的ROS产生、线粒体功能丧失和半胱天冬酶活化。此外，CYP 2 J2特异性抑制剂化合物26增强了砷对临床相关浓度ATO（1-2 μ M）的细胞毒性。含巯基的抗氧化剂N-乙酰半胱氨酸和11，12-EET均逆转了两种药物的协同效应。总之，这些数据表明，11，12-EET通过涉及诱导抗氧化蛋白和减弱ROS介导的线粒体功能障碍的机制抑制ATO诱导的细胞凋亡。
Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 mu M). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.