c-Jun NH2-terminal kinase activation contributes to hypoxia-inducible factor 1α-dependent P-glycoprotein expression in hypoxia
c-Jun NH2-terminal kinase activation contributes to hypoxia-inducible factor 1α-dependent P-glycoprotein expression in hypoxia
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DOI：
10.1158/0008-5472.can-04-1919
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Taylor, CT
中科院分区：
文献类型：
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作者：
Comerford, KM;Cummins, EP;Taylor, CT
我们先前已经证明，缺氧会增加P-糖蛋白的表达，进而增加肿瘤细胞主动分泌化疗药物的能力，并可能导致肿瘤耐药。这一事件是通过低氧诱导因子(HIF-1)介导的。在这里，我们研究了应激激活蛋白激酶c-jun NH2末端激酶(JNK)在这些事件背后的信号机制中的作用。低氧在体外和体内均能激活JNK活性。过度表达的丝裂原活化蛋白激酶(MAPK)激酶(Mekk-1)优先激活JNK，以非相加的方式模拟低氧诱导的MDR1启动子的活性以及MDR1mRNA和P-糖蛋白的表达。此外，JNK抑制剂SP600125选择性和特异性地抑制缺氧和Mekk-1诱导的mdr1启动子活性，并呈剂量依赖关系。抑制JNK还逆转了缺氧和Mekk-1诱导的HIF-1依赖的报告基因的活性。Mekk-1诱导的mdr1表达依赖于HIF-1的功能结合部位(缺氧反应元件)。SP600125可抑制低氧诱导的HIF-1 DNA结合和转录激活，说明低氧诱导的HIF-1信号依赖于JNK的激活。由于已有报道称，在低氧条件下，活性氧物种会增加，并与JNK的激活有关，因此我们研究了它们在信号转导这一反应中的作用。外源H_2O_2的加入足以激活JNK，而活性氧清除剂对低氧诱导的JNK或HIF-1的激活没有影响。因此，低氧诱导的mdr1表达依赖于HIF-1的激活，至少部分依赖于JNK激活的信号转导。此外，这些事件与活性氧中间体的产生无关。因此，JNK可能是预防肿瘤化疗耐药的一个治疗靶点。
We previously have shown that hypoxia increases the expression of P-glycoprotein, which in turn increases tumor cell capacity to actively extrude chemotherapeutic agents and may contribute to tumor drug resistance. This event is mediated through the hypoxia-inducible factor (HIF-1). Here, we investigated the role of the stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) in the signaling mechanisms underlying these events. Hypoxia activates JNK activity in vitro and in vivo. Overexpression of mitogen-activated protein kinase (MAPK) kinase kinase (MEKK-1), which preferentially activates JNK, mimics, in a nonadditive way, hypoxia-induced activity of the MDR1 promoter and expression of MDR1 mRNA and P-glycoprotein. Furthermore, the JNK inhibitor SP600125 selectively and specifically inhibits hypoxia- and MEKK-1-induced MDR1 promoter activity in a dose-dependent manner. JNK inhibition also reversed hypoxia- and MEKK-1-induced activity of an HIF-1-dependent reporter gene. MEKK-1-induced MDR1 expression depends on a functional HIF-1 binding site (hypoxia-responsive element). Hypoxia-but not cobalt chloride-dependent HIF-1-DNA binding and transcriptional activation was inhibited by SP600125, indicating that hypoxia-induced signaling to HIF-1 depends on JNK activation. Because it has been reported that reactive oxygen species are increased in hypoxia and related to JNK activation, we investigated their role in signaling this response. Whereas exogenous addition of H2O2 was sufficient to activate JNK, reactive oxygen species scavengers were without effect on hypoxia-induced JNK or HIF-1 activation. Thus, hypoxia-elicited MDR1 expression, which depends on HIF-1 activation, depends at least in part on signaling via activation of JNK. Furthermore, these events are independent of the generation of reactive oxygen intermediates. Thus, JNK may represent a therapeutic target in the prevention of tumor resistance to chemotherapeutic treatment.