Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B
文献类型：期刊论文
| 作者 | Wang, Zheng2,3; Li, Zeng-xia2; Zhao, Wen-cao4; Huang, Hong-bo5; Wang, Jia-qi2; Zhang, Hao6; Lu, Jun-yan6; Wang, Rui-na2; Li, Wei7; Cheng, Zhao2 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2020-08-14 |
| 页码 | 13 |
| 关键词 | grincamycin B marine natural product isocitrate dehydrogenase 1 apoptosis ER stress intracellular ROS Zebrafish embryos hematological malignancies |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-020-0491-6 |
| 通讯作者 | Dang, Yong-jun(yongjundang@fudan.edu.cn) |
| 英文摘要 | Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomyceteStreptomycesstrains 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 ofN-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. |
| WOS关键词 | MUTANT IDH1 ; HEMATOPOIESIS ; INHIBITORS ; GLYCOSIDES ; MUTATIONS ; GROWTH |
| 资助项目 | National Key Research and Development Program of China[2018YFC0310900] ; National Natural Science Foundation of China[21877016] ; National Natural Science Foundation of China[81372768] ; National Natural Science Foundation of China[21572038] ; National Natural Science Foundation of China[21672248] ; National Natural Science Foundation of China[81820108030] ; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology[LMDBKF201704] ; Fund of the State Key Laboratory of Bioorganic and Natural Products Chemistry[SKLBNPC16233] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000559690000001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292320]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Dang, Yong-jun |
| 作者单位 | 1.Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA 2.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China 3.Fudan Univ, Sch Life Sci, Inst Genet, State Key Lab Genet Engn, Shanghai 200438, Peoples R China 4.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth,Shanghai Inst Biol Sci, Key Lab Tissue Microenvironm & Tumor,CAS Ctr Exce, Shanghai 200031, Peoples R China 5.Chinese Acad Sci, South China Sea Inst Oceanol, CAS Key Lab Trop Marine Bioresources & Ecol, Guangdong Key Lab Marine Mat Med, Guangzhou 510301, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China 8.Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China 9.Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Inst Life Sci, Chongqing 400016, Peoples R China 10.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266003, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Zheng,Li, Zeng-xia,Zhao, Wen-cao,et al. Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B[J]. ACTA PHARMACOLOGICA SINICA,2020:13. |
| APA | Wang, Zheng.,Li, Zeng-xia.,Zhao, Wen-cao.,Huang, Hong-bo.,Wang, Jia-qi.,...&Dang, Yong-jun.(2020).Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | Wang, Zheng,et al."Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B".ACTA PHARMACOLOGICA SINICA (2020):13. |
入库方式： OAI收割
来源：上海药物研究所
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