Role of the p38 MAPK pathway in cisplatin-based therapy
Role of the p38 MAPK pathway in cisplatin-based therapy
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DOI：
10.1038/sj.onc.1206608
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发表时间：
2003-06-26
期刊：
影响因子：
8
通讯作者：
Sánchez-Prieto, R
中科院分区：
文献类型：
--
作者：
Losa, JH;Cobo, CP;Sánchez-Prieto, R
p38 MAPK参与了对癌症治疗的反应。为了确定p38 MAPK的激活是否对癌症治疗具有特异性，我们在几种人类细胞系中研究了p38 MAPK对几种化疗药物（如顺铂、阿霉素和紫杉醇）的激活。在暴露于几种化疗药物后，使用特异性磷抗体测量p38 MAPK的激活。在所有测试的细胞系中，只有顺铂能够激活p38 MAPK。此外，其他铂类化合物如移植素和氯化铂（IV）可以诱导p38 MAPK活化。这种激活的动力学是p38 MAPK对顺铂反应的生物学作用的关键事件，正如我们从移植和顺铂治疗后观察到的差异中得出的结论。p38 MAPK的激活与细胞系的起源或遗传改变无关，似乎是通过上游激活因子MKK6和MKK3介导的。虽然α / β亚型主要被激活，但我们也证明p38 MAPK家族的其他成员在293 t中过表达时也容易被顺铂激活。最后，用特异性抑制剂（SB 203580和SKF 86002）预处理诱导顺铂耐药表型。此外，SAPK通路的低激活与头颈癌的耐药表型相关，这在我们的头颈癌实验模型中得到证实。因此，我们得出结论，p38 MAPK通路是具有临床意义的顺铂治疗的特异性靶点。
p38 MAPK has been implicated in the response to cancer therapy. To determine whether the activation of p38 MAPK could be specific to cancer therapy, we investigated the activation of p38 MAPK in response to several chemotherapeutic agents, such as cisplatin, doxorubicin and taxol in several human cell lines. Activation of p38 MAPK was measured after exposure to several chemotherapeutic agents, using specific phosphoantibodies. Only cisplatin was able to activate p38 MAPK in all the cell lines tested. Furthermore, other platinum compounds such as transplatin and platinum (IV) chloride can induce activation of p38 MAPK. The kinetics of this activation is a key event in the biological role of p38 MAPK in response to cisplatin, as we conclude from the differences observed after treatment with transplatin and cisplatin. The p38 MAPK activation is independent of the origin or genetic alterations of the cell lines and seems to be mediated through both upstream activators MKK6 and MKK3. Although the isoforms alpha/beta are mainly activated, we also demonstrated that other members of the p38 MAPK family were susceptible to activation by cisplatin when they were overexpressed in 293 T. Finally, pretreatment with specific inhibitors (SB 203580 and SKF 86002) induces a resistant phenotype in response to cisplatin. Furthermore, low activation of this SAPK pathway correlates with a resistant phenotype as demonstrated in our experimental model of head and neck cancer. Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications.