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首页> 外文期刊>Cell death and differentiation >ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis
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ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis

机译：ROS依赖的JNK激活将p53转化为致癌基因的有效抑制剂，导致强大的细胞凋亡

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摘要

Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced growth arrest/senescence to apoptosis. We identified several survival oncogenes inhibited by p53 in JNK-dependent manner, including Mcl1, PI3K, elF4E, as well as p53 inhibitors Wip1 and MdmX. Further, we show that Wip1 is one of the crucial executors downstream of JNK whose ablation confers the enhanced and sustained p53 transcriptional response contributing to cell death. Our study provides novel insights for manipulating p53 response in a controlled way. Further, our results may enable new pharmacological strategy to exploit abnormally high ROS level, often linked with higher aggressiveness in cancer, to selectively kill cancer cells upon pharmacological reactivation of p53.
机译：挽救p53抑癌药是一种有吸引力的癌症治疗方法。然而，药理激活的p53可以诱导从细胞死亡到生长停滞和DNA修复的多种反应，这限制了p53激活药物在临床中的有效应用。阐明在p53激活后定义生物学结果的分子机制仍然是p53领域的一大挑战。在这里，我们报道了同时发生的p53药理激活和硫氧还蛋白还原酶抑制作用，随后产生活性氧（ROS），导致癌细胞的合成致死性。 ROS促进c-Jun N末端激酶（JNK）的激活和DNA损伤反应，从而与p53建立正反馈回路。这将p53诱导的生长停滞/衰老转变为凋亡。我们鉴定了几种以JNK依赖性方式被p53抑制的存活癌基因，包括Mcl1，PI3K，eIF4E以及p53抑制剂Wip1和MdmX。此外，我们显示Wip1是JNK下游的重要执行者之一，其消融赋予增强和持续的p53转录反应，从而导致细胞死亡。我们的研究为以受控方式操纵p53反应提供了新颖的见解。此外，我们的结果可能使新的药理策略能够利用异常高的ROS水平（通常与更高的癌症侵袭性相关）来利用p53的药理学活化选择性杀死癌细胞。

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