The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy
The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy
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DOI：
10.1007/s00280-016-3225-1
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发表时间：
2017-02-01
影响因子：
3
通讯作者：
Simpkins, Henry
中科院分区：
文献类型：
--
作者：
Chen, Jianli;Solomides, Charalambos;Simpkins, Henry
在卵巢、宫颈和肺细胞系中研究了Nrf 2及其在控制醛酮还原酶AKR家族水平中的作用，该家族与铂类化疗的耐药性有关。制备了来自不同肿瘤来源的细胞的Nrf 2 shRNA敲除，以确定该因子在产生铂类化疗耐药性中的作用。Nrf 2敲除导致AKR 1C 1显著降低，AKR 1C 2和较小程度的AKR 1C 3。此外，所有其他候选酶GST Pl和TRXl均降低，但它们的作用难以与细胞毒性相关。顺铂治疗后，Nrf 2敲除表现出线粒体膜去极化和ROS产生的显著增加，宫颈ME 180 R敲除表现出最大的影响（ME 180 R和SKOV 3细胞中AKR 1C 1和AKR 1C 2水平降低至接近零）。奥沙利铂倾向于与顺铂平行，除了它显著刺激O-2（-）产生，而不是通过奥沙利铂处理ME 180 R细胞。pJNK/p38通路与顺铂细胞毒性有关，在SKOV 3中观察到pJNK的显著磷酸化，在SKOV 3敲除中观察到ME 180 R和p38。在Nrf 2敲除（Crf 38、Srf 6、Arf 5）中，ATF 2的磷酸化降低，这可能影响其与JNK和p38的相互作用。奥沙利铂治疗显示对JNK/p38通路的影响极小，表明其作用模式不同，尽管ROS产生似乎是两种药物的初始步骤。Nrf 2控制许多不同的候选基因;然而，它确实通过AKR家族显著调节顺铂耐药性。这涉及ROS的产生和pJNK/p38通路的激活，并涉及ATF 2。
Nrf2 and its role in controlling levels of the AKR family of aldo-keto reductases which have been implicated in resistance to platinum-based chemotherapy was studied in ovarian, cervical and lung cell lines.Nrf2 shRNA knockdowns of cells from different tumor origins were prepared to determine the role of this factor in producing resistance to platinum chemotherapy.Nrf2 knockdowns resulted in marked decreases in AKR1C1, AKR1C2 and to a lesser extent AKR1C3. Additionally, all other candidate enzymes GST pi and TRX1 were decreased, but their role was difficult to correlate to cytotoxicity. Nrf2 knockdowns exhibited marked increases in mitochondrial membrane depolarization and ROS production following cisplatin treatment, with the cervical ME180R knockdowns exhibiting the greatest effect (AKR1C1 and AKR1C2 levels were decreased in the ME180R and SKOV3 cells to near zero). Oxaliplatin tended to parallel cisplatin, except it markedly stimulated O-2 (-) production not by oxaliplatin treatment of the ME180R cells. The pJNK/p38 pathway has been implicated in cisplatin cytotoxicity, and significant phosphorylation of pJNK was observed in the SKOV3 and ME180R and p38 in the SKOV3 knockdowns. Phosphorylation of ATF2 was decreased in the Nrf2 knockdowns (Crf38, Srf6, Arf5) which could affect its interaction with JNK and p38. Oxaliplatin treatment showed minimal effects on the JNK/p38 pathway, showing that its mode of action is different although ROS generation appeared an initial step with both drugs.Nrf2 controls a multitude of different candidate genes; however, it did markedly modulate cisplatin resistance through the AKR family. This involved ROS production and activation of the pJNK/p38 pathway with involvement of ATF2.