Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK.
Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK.
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DOI：
10.1002/emmm.201302732
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发表时间：
2013-11
影响因子：
11.1
通讯作者：
Nebreda, Angel R.
中科院分区：
文献类型：
--
作者：
Pereira, Lorena;Igea, Ana;Canovas, Begona;Dolado, Ignacio;Nebreda, Angel R.
p38 MAPK通路是许多细胞反应的重要调节因子。p38 MAPK信号传导负调节上皮细胞转化，但增强的p38 MAPK活性也与某些肿瘤类型的不良临床预后相关。在这里，我们提供的遗传和药理学证据表明，p38 MAPK抑制与化疗药物顺铂杀死肿瘤细胞。我们发现，p38 MAPK抑制导致ROS上调，这反过来又激活JNK途径通过磷酸酶失活，敏感的人肿瘤细胞顺铂诱导的凋亡。使用小鼠乳腺癌模型，我们证实，抑制p38 MAPK与顺铂治疗合作，以减少体内肿瘤的大小和恶性程度。综上所述，我们的研究结果说明了p38 MAPK的一种新功能，有助于肿瘤细胞在化疗药物治疗中存活，并揭示了p38 MAPK抑制剂与顺铂的组合可以潜在地用于癌症治疗。
The p38 MAPK pathway is an important regulator of many cellular responses. It is well established that p38 MAPK signalling negatively regulates epithelial cell transformation, but enhanced p38 MAPK activity has been also correlated with bad clinical prognosis in some tumour types. Here, we provide genetic and pharmacological evidence showing that p38 MAPK inhibition cooperates with the chemotherapeutic agent cisplatin to kill tumour cells. We show that p38 MAPK inhibition results in ROS upregulation, which in turn activates the JNK pathway via inactivation of phosphatases, sensitizing human tumour cells to cisplatin-induced apoptosis. Using a mouse model for breast cancer, we confirm that inhibition of p38 MAPK cooperates with cisplatin treatment to reduce tumour size and malignancy in vivo. Taken together, our results illustrate a new function of p38 MAPK that helps tumour cells to survive chemotherapeutic drug treatments, and reveal that the combination of p38 MAPK inhibitors with cisplatin can be potentially exploited for cancer therapy.
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影响因子：
11.2
作者：
Chen L;Mayer JA;Krisko TI;Speers CW;Wang T;Hilsenbeck SG;Brown PH
通讯作者：
Brown PH
影响因子：
30.8
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
影响因子：
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作者：
Demuth, Tim;Reavie, Linsey B.;Berens, Michael E.
通讯作者：
Berens, Michael E.
影响因子：
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作者：
Dolado, Ignacio;Swat, Aneta;Nebreda, Angel R.
通讯作者：
Nebreda, Angel R.
影响因子：
11.4
作者：
Joaquin, Manel;Gubern, Albert;Gonzalez-Nunez, Daniel;Josue Ruiz, E.;Ferreiro, Isabel;de Nadal, Eulalia;Nebreda, Angel R.;Posas, Francesc
通讯作者：
Posas, Francesc