文章：

三氧化二砷与p97抑制剂通过靶向新生多肽并激活ZAKα–JNK通路协同抗急性髓系白血病

Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα–JNK pathway

原文发布日期：2024-08-09 

英文摘要：

Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of the PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit to non-APL acute myeloid leukemia (AML) patients and exhibits limited efficacy when used in combination with other agents. Here, we explored the general toxicity mechanisms of ATO in APL and potential drugs that could be combined with ATO to exhibit synergistic lethal effects on other AML. We demonstrated that PML-RARα degradation and ROS upregulation were insufficient to cause APL cell death. Based on the protein synthesis of different AML cells and their sensitivity to ATO, we established a correlation between ATO-induced cell death and protein synthesis. Our findings indicated that ATO induced cell death by damaging nascent polypeptides and causing ribosome stalling, accompanied by the activation of the ZAKα-JNK pathway. Furthermore, ATO-induced stress activated the GCN2–ATF4 pathway, and ribosome-associated quality control cleared damaged proteins with the assistance of p97. Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML. 

摘要翻译：

三氧化二砷（ATO）在治疗急性早幼粒细胞白血病（APL）方面表现出显著疗效，其主要通过促进PML-RARα融合蛋白的降解实现。然而，单用ATO无法为非APL型急性髓系白血病（AML）患者带来生存获益，且与其他药物联用时疗效有限。本研究探索了ATO对APL的通用毒性作用机制，以及可能与其协同作用于其他AML亚型的潜在联合药物。我们发现PML-RARα降解和ROS上调并不足以导致APL细胞死亡。通过分析不同AML细胞的蛋白质合成能力及其对ATO的敏感性，我们确立了ATO诱导细胞死亡与蛋白质合成之间的关联。研究结果表明，ATO通过破坏新生多肽链、引起核糖体停滞并激活ZAKα-JNK通路来诱导细胞死亡。此外，ATO诱导的应激状态激活了GCN2–ATF4通路，而核糖体关联质量控制机制在p97蛋白协助下清除了受损蛋白质。重要的是，数据表明抑制p97可增强ATO杀伤AML细胞的效力。这些发现为筛选最优合成致死药物以增强ATO对非APL型AML的治疗效果奠定了基础。

原文链接：

Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα–JNK pathway