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Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B

Authors: Zheng Wang1,2, Zeng-xia Li1, Wen-cao Zhao3, Hong-bo Huang4, Jia-qi Wang1, Hao Zhang5, Jun-yan Lu5, Rui-na Wang1, Wei Li6, Zhao Cheng1, Wen-long Xu1, Di Zhu1, Li-sha Zhou7, Wei Jiang1, Long Yu2, Jun-yan Liu8, Cheng Luo5, Heng Zhu1,9, Dan Ye7, Wei-jun Pan3, Jian-hua Ju4, Yong-jun Dang1,10
1 Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
2 State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, China
3 Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, China
4 CAS Key Laboratory of Tropical Marine Bio- resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China
5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
6 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
7 Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
8 Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
9 Department of Pharmacology & Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
10 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
Correspondence to: Yong-jun Dang: yongjundang@fudan.edu.cn,
DOI: 10.1038/s41401-020-0491-6
Received: 5 May 2020
Accepted: 22 July 2020
Advance online: 14 August 2020

Abstract

Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomycete Streptomyces strains that have potent antitumor activities, but their antitumor mechanisms remain unknown. In this study, we tried to identify the cellular target of grincamycin B (GCN B), one of most dominant and active secondary metabolites, using a combined strategy. We showed that GCN B-selective-induced apoptosis of human acute promyelocytic leukemia (APL) cell line NB4 through increase of ER stress and intracellular reactive oxygen species (ROS) accumulation. Using a strategy of combining phenotype, transcriptomics and protein microarray approaches, we identified that isocitrate dehydrogenase 1(IDH1) was the putative target of GCN B, and confirmed that GCNs were a subset of selective inhibitors targeting both wild-type and mutant IDH1 in vitro. It is well-known that IDH1 converts isocitrate to 2-oxoglutarate (2-OG), maintaining intracellular 2-OG homeostasis. IDH1 and its mutant as the target of GCN B were validated in NB4 cells and zebrafish model. Knockdown of IDH1 in NB4 cells caused the similar phenotype as GCN B treatment, and supplementation of N-acetylcysteine partially rescued the apoptosis caused by IDH1 interference in NB4 cells. In zebrafish model, GCN B effectively restored myeloid abnormality caused by overexpression of mutant IDH1(R132C). Taken together, we demonstrate that IDH1 is one of the antitumor targets of GCNs, suggesting wild-type IDH1 may be a potential target for hematological malignancies intervention in the future.
Keywords: grincamycin B; marine natural product; isocitrate dehydrogenase 1; apoptosis; ER stress; intracellular ROS; Zebrafish embryos; hematological malignancies

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