The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells
The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells
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DOI：
10.1038/onc.2016.384
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发表时间：
2017-04-06
期刊：
影响因子：
8
通讯作者：
Chen, C. M.
中科院分区：
文献类型：
--
作者：
Ma, S. Q.;Cao, B. R.;Chen, C. M.
RAF-1在细胞抗凋亡中发挥重要作用。到目前为止，还没有确凿的证据表明Raf-1突变与癌症的发生有关。在对Raf-1信号的进一步研究过程中，我们报道了Raf-1过度磷酸化抑制其下游丝裂原活化蛋白激酶1/2(MEK1/2)的活性，并提出了Raf-1负反馈调控的模型。在这里，我们表明，在一些癌细胞中没有过度磷酸化，这导致了激酶活性的增加，并增强了抗凋亡能力。抑制Raf-1或ALG-2的表达导致细胞凋亡信号调节激酶1/c-jun氨基末端激酶(ASK1/JNK)信号的激活，细胞对化疗药物的敏感性，表明Raf-1抑制ASK1/JNK的凋亡信号是由ALG-2介导的。以往的研究表明，细胞外信号调节蛋白1/2(ERK1/2)参与了Raf-1的过度磷酸化。然而，我们的证据表明，当ERK1/2被激活并且Raf-1基因没有突变时，Raf-1在这些细胞中不被过度磷酸化，表明ERK1/2不是这些癌细胞系中Raf-1过度磷酸化的原因。令人惊讶的是，我们还发现，在正常的组织培养条件下，Raf-1不是MEK1/2激活所必需的激酶，但在诱导细胞凋亡的条件下，Raf-1是MEK1/2激活所必需的。我们的研究表明，虽然Raf-1基因没有突变，但Raf-1激酶反馈调节的异常增强了其抗凋亡功能，Raf-1仍然可以作为药物靶点来增加这些癌细胞对化疗或放疗的敏感性。
Raf-1 has an important role in cellular antiapoptosis. So far, there is no solid evidence that shows that Raf-1 mutation is associated with cancer development. In the course of further study of Raf-1 signaling, we have reported that Raf-1 hyperphosphorylation inhibits its kinase activity toward its downstream mitogen-activated protein kinase kinase 1/2 (MEK1/2) and proposed a model for negative feedback regulation of Raf-1. Here, we show that there is no hyperphosphorylation in some cancer cells, which results in increased kinase activity and enhances the antiapoptotic ability. Inhibition of either Raf-1 or ALG-2 (apoptosis-linked gene 2) expression results in apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase (ASK1/JNK) signaling activation, and cell sensitivity to chemotherapeutic reagents, indicating that inhibition of ASK1/JNK apoptotic signaling by Raf-1 is mediated by ALG-2. A previous report indicated that extracellular signal-regulated kinase 1/2 (ERK1/2) were responsible for Raf-1 hyperphosphorylation. However, our evidence shows that when ERK1/2 are activated and the Raf-1 gene is not mutated, Raf-1 is not hyperphosphorylated in these cells, indicating that ERK1/2 are not responsible for the Raf-1 hyperphosphorylation in these cancer cell lines. Surprisingly, we also found that Raf-1 is not a necessary kinase for MEK1/2 activation under normal tissue culture conditions, but is required for MEK1/2 activation under apoptosis-inducing conditions. Our research demonstrates that although Raf-1 gene is not mutated, an abnormality of Raf-1 kinase feedback regulation enhances its antiapoptotic function, and Raf-1 can still be a pharmaceutical target to increase chemotherapy or radiotherapy sensitivity in these cancer cells.