Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress
Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress
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DOI：
10.1128/mcb.21.20.6913-6926.2001
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发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Levitzki, A
中科院分区：
文献类型：
--
作者：
Benhar, M;Dalyot, I;Levitzki, A
许多原发性肿瘤以及转化的细胞系显示出对化疗药物和辐射的高敏感性。这种敏感性背后的分子机制在很大程度上是未知的。在这里，我们表明，敏感的转化细胞的应激刺激是由于增强的c-Jun N-末端激酶（JNK）和p38氮激活蛋白激酶途径。抗肿瘤药物顺铂（CDDP）和其他应激药物对这些通路的激活显著增强，并且在过度表达表皮生长因子受体、HER 1 -2激酶或致癌Ras的NIH 3 T3细胞中，诱导的应激剂量低于非转化NIH 3 T3细胞。通过特异性抑制剂抑制应激激酶活性可减少转化细胞中CDDP介导的细胞死亡，而应激激酶途径的过度激活则增加细胞死亡。应激激酶的增强是由不同癌基因转化的细胞的共同特征，包括源自人类肿瘤的细胞，并且在此显示与特定转化癌蛋白的活性无关。我们进一步表明，在转化细胞中的应激激酶的增强的机制涉及活性氧（ROS），其生产在这些细胞中升高。JNK/p38活化被抗氧化剂抑制，特别是被线粒体呼吸链和NADPH氧化酶的抑制剂抑制。相反，通过人工升高未转化的NIH 3 T3细胞中的ROS水平，我们能够诱导JNK/p38活化的增强。两者合计，我们的研究结果表明，ROS依赖性增强的应激激酶途径占敏感的转化细胞的压力和抗癌药物。
Many primary tumors as well as transformed cell lines display high sensitivity to chemotherapeutic drugs and radiation. The molecular mechanisms that underlie this sensitivity are largely unknown. Here we show that the sensitization of transformed cells to stress stimuli is due to the potentiation of the c-Jun N-terminal kinase (JNK) and p38 nitrogen-activated protein kinase pathways. Activation of these pathways by the antitumor drug cis-platin (CDDP) and by other stress agents is markedly enhanced and is induced by lower stress doses in NIH 3T3 cells overexpressing epidermal growth factor receptor, HER1-2 kinase, or oncogenic Ras than in nontransformed NIH 3T3 cells. Inhibition of stress kinase activity by specific inhibitors reduces CDDP-mediated cell death in transformed cells, whereas overactivation of stress kinase pathways augments cells death. Potentiation of stress kinases is a common feature of cells transformed by different oncogenes, including cells derived front human tumors, and is shown here to be independent of the activity of the particular transforming oncoprotein. We further show that the mechanism that underlies potentiation of stress kinases in transformed cells involves reactive oxygen species (ROS), whose production is elevated in these cells. JNK/p38 activation is inhibited by antioxidants and in particular by inhibitors of the mitochondrial respiratory chain and NADPH oxidase. Conversely, by artificially elevating ROS levels in nontransformed NIH 3T3 cells we were able to induce potentiation of JNK/p38 activation. Taken together, our findings suggest that ROS-dependent potentiation of stress kinase pathways accounts for the sensitization of transformed cells to stress and anticancer drugs.