2. Academic Validation
  3. Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα-JNK pathway

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

  • Cancer Gene Ther. 2024 Aug 9. doi: 10.1038/s41417-024-00818-z.
Shufeng Xie # 1,  Hui Liu # 2,  Shouhai Zhu # 3,  Zhihong Chen # 4,  Ruiheng Wang 4,  Wenjie Zhang 5,  Huajian Xian 4,  Rufang Xiang 4 6,  Xiaoli Xia 4,  Yong Sun 4,  Jinlan Long 5,  Yuanli Wang 7,  Minghui Wang 4,  Yixin Wang 4,  Yaoyifu Yu 4,  Zixuan Huang 4,  Chaoqun Lu 4,  Zhenshu Xu 8,  Han Liu 9
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai, China. xieshufeng@sjtu.edu.cn.
  • 2 Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Oncology, Mayo Clinic, Rochester, MN, USA.
  • 4 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai, China.
  • 5 Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
  • 6 Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, China.
  • 8 Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China. zhenshuxu@yahoo.com.
  • 9 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai, China. liuhan68@sjtu.edu.cn.
  • # Contributed equally.
PMID: 39122830 DOI: 10.1038/s41417-024-00818-z
Abstract

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.

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