Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES

Yang, Fan1,2; Zhou, Hongchao1; Luo, Piao3,4,5; Jia, Lin6; Hou, Mengyun1; Huang, Jingnan2; Gao, Lin1; Zhang, Qian3,4,5; Guan, Yudong1,2; Bao, Honglei6; Zhang, Baotong2; Liu, Liping1; Zou, Chang1; Yang, Qinhe1,7; Wang, Jigang1,5; Dai, Lingyun1,2,8

2024-11-01

10.1016/j.phymed.2024.155937

PHYTOMEDICINE   影响因子和分区

0944-7113

1618-095X

Background: Chronic myeloid leukemia (CML) is driven primarily by the constitutively active BCR-ABL fusion oncoprotein. Although the development of tyrosine kinase inhibitors has markedly improved the prognosis of CML patients, it remains a significant challenge to overcome drug-resistant mutations, such as the T315I mutation of BCR-ABL, and achieve treatment-free remission in the clinic. Purpose: The identification of new intervention targets beyond BCR-ABL could provide new perspectives for future research and therapeutic intervention. A network pharmacology analysis was conducted to identify the most promising natural product with anti-CML activity. Celastrol was selected for further analysis to gain insights into its mechanism of action (MoA), with the aim of identifying potential new intervention targets for BCR-ABL T315I-mutant CML. Methods: Transcriptomic and proteomic analyses were conducted to systematically investigate the molecular MoA of celastrol in K562(T315I) cells. To identify the target proteins of celastrol, mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) was carried out, followed by validations with genetic knockdown and overexpression, cell proliferation assay, comet assay, Western blotting, celastrol probe-based in situ labeling and pull-down assay, molecular docking, and biolayer interferometry. Results: Our multi-omics analyses revealed that celastrol primarily induces DNA damage accumulation and the unfolded protein response in K562T315I cells. Among the twelve most potential celastrol targets, experimental evidence demonstrated that the direct interaction of celastrol with YY1 and HMCES increases the levels of DNA damage, leading to cell death. Conclusion: This study represents the first investigation utilizing a proteome-wide label-free target deconvolution approach, MS-CETSA, to identify the protein targets of celastrol. This study also develops a new systems pharmacology strategy. The findings provide new insights into the multifaceted mechanisms of celastrol and, more importantly, highlight the potential of targeting proteins in DNA damage and repair pathways, particularly YY1 and HMCES, to combat drug-resistant CML.

Chronic myeloid leukemia Drug resistance Celastrol DNA damage YY1 HMCES

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China["32070748","81902787","82273041"] ; GuangDong Basic and Applied Basic Research Foundation["2024A1515010300","2023B1515120036"] ; Excellent Scientific and Technological Innovation Training Program of Shenzhen[RCYX20210706092040048] ; Science and Technology Foundation of Shenzhen[JCYJ20210324115800001] ; Shenzhen Medical Research Fund[B2302051] ; Natural Science Foundation of Top Talent of SZTU[GDRC202125]

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:001313650400001

ELSEVIER GMBH

Web of Science

1.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp 1, Clin Med Coll 2,Affiliated Hosp,Dept Gen Surg,Guan, Shenzhen 518020, Peoples R China
2.Southern Univ Sci & Technol, Sch Med, Shenzhen 518020, Peoples R China
3.Southern Med Univ, Sch Tradit Chinese Med, Guangzhou 510515, Peoples R China
4.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
5.China Acad Chinese Med Sci, Inst Chinese Mat Med, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
6.Shenzhen Technol Univ, Coll Pharm, Shenzhen 518118, Peoples R China
7.Jinan Univ, Sch Tradit Chinese Med, Guangzhou 510632, Peoples R China
8.ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore

Yang, Fan,Zhou, Hongchao,Luo, Piao,et al. Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES[J]. PHYTOMEDICINE,2024,134.

Yang, Fan.,Zhou, Hongchao.,Luo, Piao.,Jia, Lin.,Hou, Mengyun.,...&Dai, Lingyun.(2024).Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES.PHYTOMEDICINE,134.

Yang, Fan,et al."Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES".PHYTOMEDICINE 134(2024).