2. Academic Validation
  3. Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES

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

  • Phytomedicine. 2024 Nov:134:155937. doi: 10.1016/j.phymed.2024.155937.
Fan Yang 1,  Hongchao Zhou 2,  Piao Luo 3,  Lin Jia 4,  Mengyun Hou 2,  Jingnan Huang 1,  Lin Gao 2,  Qian Zhang 3,  Yudong Guan 1,  Honglei Bao 4,  Baotong Zhang 5,  Liping Liu 2,  Chang Zou 2,  Qinhe Yang 6,  Jigang Wang 7,  Lingyun Dai 8
Affiliations

Affiliations

  • 1 Department of General Surgery, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China; School of Medicine, Southern University of Science and Technology, Shenzhen 518020, China.
  • 2 Department of General Surgery, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
  • 3 School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 4 College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
  • 5 School of Medicine, Southern University of Science and Technology, Shenzhen 518020, China.
  • 6 Department of General Surgery, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China; School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China. Electronic address: tyangqh@jnu.edu.cn.
  • 7 Department of General Surgery, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: jgwang@icmm.ac.cn.
  • 8 Department of General Surgery, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China; School of Medicine, Southern University of Science and Technology, Shenzhen 518020, China; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore. Electronic address: lingyun.dai@outlook.com.
PMID: 39255723 DOI: 10.1016/j.phymed.2024.155937
Abstract

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 K562T315I 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.

Keywords

Celastrol; Chronic myeloid leukemia; DNA damage; Drug resistance; HMCES; YY1.

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