Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia

doi:10.1186/s40164-024-00489-4

科研成果详情

题名	Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia
作者	Feng, Shuya1; Yuan, Yigang 1; Lin, Zihan 1; Li, Min 1; Ye, Daijiao1; Shi, Liuzhi2; Li, Danyang 1; Zhao, Min 1; Meng, Chen1; He, Xiaofei1; Wu, Shanshan 1; Xiong, Fang 3; Ye, Siyu 4; Yang, Junjun5; Zhuang, Haifeng 6; Hong, Lili 6; Gao, Shenmeng1,7
发表日期	2024-02-20
发表期刊	Experimental Hematology and Oncology 影响因子和分区
语种	英语
原始文献类型	Article ; Journal Article
关键词	Ferroptosis Glutathione peroxidase-4 AMPK Acute myeloid leukemia Hypomethylating agent
其他关键词	CANCER-CELLS ; AMPK ; APOPTOSIS ; DECITABINE ; PROTECTS ; GENE ; GPX4 ; EXPRESSION ; STRESS
摘要	BackgroundFerroptosis is a new form of nonapoptotic and iron-dependent type of cell death. Glutathione peroxidase-4 (GPX4) plays an essential role in anti-ferroptosis by reducing lipid peroxidation. Although acute myeloid leukemia (AML) cells, especially relapsed and refractory (R/R)-AML, present high GPX4 levels and enzyme activities, pharmacological inhibition of GPX4 alone has limited application in AML. Thus, whether inhibition of GPX4 combined with other therapeutic reagents has effective application in AML is largely unknown.MethodsLipid reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) assays were used to assess ferroptosis in AML cells treated with the hypomethylating agent (HMA) decitabine (DAC), ferroptosis-inducer (FIN) RAS-selective lethal 3 (RSL3), or their combination. Combination index (CI) analysis was used to assess the synergistic activity of DAC + RSL3 against AML cells. Finally, we evaluated the synergistic activity of DAC + RSL3 in murine AML and a human R/R-AML-xenografted NSG model in vivo.ResultsWe first assessed GPX4 expression and found that GPX4 levels were higher in AML cells, especially those with MLL rearrangements, than in NCs. Knockdown of GPX4 by shRNA and indirect inhibition of GPX4 enzyme activity by RSL3 robustly induced ferroptosis in AML cells. To reduce the dose of RSL3 and avoid side effects, low doses of DAC (0.5 mu M) and RSL3 (0.05 mu M) synergistically facilitate ferroptosis by inhibiting the AMP-activated protein kinase (AMPK)-SLC7A11-GPX4 axis. Knockdown of AMPK by shRNA enhanced ferroptosis, and overexpression of SLC7A11 and GPX4 rescued DAC + RSL3-induced anti-leukemogenesis. Mechanistically, DAC increased the expression of MAGEA6 by reducing MAGEA6 promoter hypermethylation. Overexpression of MAGEA6 induced the degradation of AMPK, suggesting that DAC inhibits the AMPK-SLC7A11-GPX4 axis by increasing MAGEA6 expression. In addition, DAC + RSL3 synergistically reduced leukemic burden and extended overall survival compared with either DAC or RSL3 treatment in the MLL-AF9-transformed murine model. Finally, DAC + RSL3 synergistically reduced viability in untreated and R/R-AML cells and extended overall survival in two R/R-AML-xenografted NSG mouse models.ConclusionsOur study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.
资助项目	National Natural Science Foundation of China [81971991, 82300194]; Zhejiang Provincial Natural Science Foundation of China [Y23H080009, LY19H080003]; Discipline Cluster of Oncology of Wenzhou Medical University of China [z2-2023021]
出版者	BMC
ISSN	2162-3619
EISSN	2162-3619
卷号	13 期号:1
DOI	10.1186/s40164-024-00489-4
页数	20
WOS类目	Oncology ; Hematology
WOS研究方向	Oncology ; Hematology
WOS记录号	WOS:001169154500001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	38378601
SCOPUSEID	2-s2.0-85185466043
通讯作者地址	[Gao, Shenmeng]Medical Research Center,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China ; [Hong, Lili]Department of Clinical Hematology and Transfusion,The First Affiliated Hospital of Zhejiang Chinese Medical University,54 Post Road, Zhejiang Province,Hangzhou,China
Scopus学科分类	Hematology;Oncology;Cancer Research
SCOPUS_ID	SCOPUS_ID:85185466043
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/209413
专题	附属第一医院第一临床医学院（信息与工程学院）、附属第一医院附属第二医院第二临床医学院、附属第二医院、育英儿童医院第一临床医学院（信息与工程学院）、附属第一医院_临床检验诊断学
通讯作者	Hong, Lili; Gao, Shenmeng
作者单位	1.Medical Research Center,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China; 2.Department of Clinical Laboratory,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,China; 3.The Children’s Hospital of Zhejiang University School of Medicine,3333 Binsheng Road, Zhejiang Province,Hangzhou,310051,China; 4.School of Marine Sciences,Ningbo University,818 Fenghua Road, Jiangbei District, Zhejiang Province,Ningbo,China; 5.Department of Laboratory Medicine,The Second Affiliated Hospital,Yuying Children’s Hospital of Wenzhou Medical University,109 Xuanyuanxi Road, Zhejiang Province,Wenzhou,China; 6.Department of Clinical Hematology and Transfusion,The First Affiliated Hospital of Zhejiang Chinese Medical University,54 Post Road, Zhejiang Province,Hangzhou,China; 7.The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou,the Second Affiliated Hospital,Yuying Children’s Hospital of Wenzhou Medical University,109 Xuanyuanxi Road, Zhejiang Province,Wenzhou,China
第一作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院
通讯作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Feng, Shuya,Yuan, Yigang,Lin, Zihan,et al. Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia[J]. Experimental Hematology and Oncology,2024,13(1).
APA	Feng, Shuya., Yuan, Yigang., Lin, Zihan., Li, Min., Ye, Daijiao., ... & Gao, Shenmeng. (2024). Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia. Experimental Hematology and Oncology, 13(1).
MLA	Feng, Shuya,et al."Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia".Experimental Hematology and Oncology 13.1(2024).