Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance
Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance
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DOI：
10.1158/0008-5472.can-06-1280
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Gen Sheng
中科院分区：
文献类型：
--
作者：
Wang, Zhaoqing;Xu, Jing;Wu, Gen Sheng
丝裂原活化蛋白激酶（MAPK）磷酸酶（MKP）-1是MKP家族的一员，负性调节MAPK信号传导。MKP-1与细胞对应激刺激（包括抗癌治疗）的存活有关，但其在顺铂耐药性中的作用尚未完全了解。在这里，我们表明，顺铂诱导MKP-1在几个人癌细胞系。顺铂通过细胞外信号调节激酶（ERK）调控的转录机制诱导MKP-1的表达。过表达MKP-1可使人肺癌细胞对顺铂产生耐药。相反，通过小干扰RNA沉默下调MKP-1使人肺癌细胞对顺铂诱导的细胞死亡敏感。使用MKP-1基因敲除小鼠的原代小鼠胚胎成纤维细胞（MEF），我们发现顺铂诱导MKP-1与c-Jun NH 2-末端激酶（JNK）失活相关，但与ERK和p38无关。此外，顺铂诱导的凋亡在MKP-1（-/-）MEFs中显著，而这种变化在MKP-1（+/+）MEFs中最小。更重要的是，顺铂诱导的细胞死亡是通过阻断JNK而不是ERK和p38活性来抑制的。总的来说，我们的研究结果确立了JNK在顺铂诱导的细胞凋亡中的关键作用，并表明MKP-1是顺铂耐药所必需的。
Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is a member of the MKP family that negatively regulates MAPK signaling. MKP-1 has been implicated in cell survival in response to stressful stimuli, including anticancer treatment, but its role in cisplatin resistance is not fully understood. Here, we show that cisplatin induces MKP-1 in several human cancer cell lines. Induction of MKP-1 by cisplatin was through the transcriptional mechanism regulated by extracellular signal-regulated kinase (ERK). Overexpression of MKP-1 rendered human lung cancer cells resistant to cisplatin. Conversely, down-regulation of MKP-1 by small interfering RNA silencing sensitized human lung cancer cells to cisplatin-induced cell death. Using primary mouse embryonic fibroblasts (MEF) from MKP-1 knockout mice, we show that induction of MKP-1 by cisplatin correlates with inactivation of c-Jun NH2-terminal kinase (JNK) but not ERK and p38. Furthermore, apoptosis induced by cisplatin was significant in MKP-1(-/-) MEFs, whereas such change was minimal in MKP-1(+/+) MEFs. More importantly, cisplatin-induced cell death is inhibited by blocking JNK but not ERK and p38 activities. Collectively, our results establish a critical role of JNK in cisplatin-induced apoptosis and suggest that MKP-1 is required for cisplatin resistance.