The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide
The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide
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DOI：
10.1016/s0006-2952(03)00255-7
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发表时间：
2003-08-01
影响因子：
5.8
通讯作者：
Chambers, TC
中科院分区：
文献类型：
--
作者：
Brantley-Finley, C;Lyle, CS;Chambers, TC
评估抗癌药物作用中涉及的特定的细胞凋亡和生存通路对于了解药物机制和耐药模式，以提高化疗的益处是重要的。为了更好地研究丝裂原活化蛋白激酶，包括JNK和ERK，以及肿瘤抑制因子P53在肿瘤细胞对化疗的反应中的作用，我们比较了三种结构和功能不同的抗肿瘤药物对这些途径的影响。使用的药物浓度相当于使细胞增殖减少50%所需浓度的50倍。长春花碱、阿霉素或依托泊苷(VP-16)诱导KB-3癌细胞凋亡，其PARP裂解、caspase3激活和线粒体细胞色素c释放的动力学特征相似。三种药物均能强烈激活JNK，但只有长春花碱能诱导c-Jun磷酸化和AP-1激活。SP600125抑制JNK对药物诱导的细胞毒性的保护作用。在阿霉素或VP-16作用下，长春花碱可使ERK失活，而ERK不受影响。用MEK抑制剂U0126抑制ERK信号转导可增强长春花碱和阿霉素的细胞毒作用，但不能增强VP-16的细胞毒作用。长春花碱诱导P53表达下调，化学抑制P53增强长春花碱诱导的细胞死亡，提示P53具有保护作用。相比之下，阿霉素和VP-16可诱导P53的表达。抑制P53可减少药物诱导的细胞死亡，提示P53具有促凋亡作用。这些结果强调了几个关键的信号转导通路在关键抗肿瘤药物的作用机制中所扮演的不同角色，并提出了以上下文相关的方式具体增强它们的效果的方法。此外，JNK的激活可以在没有c-Jun磷酸化或AP-1激活的情况下发生，这一新的发现对于我们理解JNK的功能具有重要的意义。(C)2003 Elsevier Science Inc.保留所有权利。
Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53. and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context- dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function. (C) 2003 Elsevier Science Inc. All rights reserved.