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; Li, Zeng-xia; Zhao, Wen-cao; Huang, Hong-bo; Wang, Jia-qi; Zhang, Hao; Lu, Jun-yan; Wang, Rui-na; Li, Wei5; Cheng, Zhao |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 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 |
| 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. |
| 资助机构 | National Key Research and Development Program of China [2018YFC0310900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21877016, 81372768, 21572038, 21672248, 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] ; National Key Research and Development Program of China [2018YFC0310900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21877016, 81372768, 21572038, 21672248, 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] |
| 源URL | [http://ir.scsio.ac.cn/handle/344004/18369]  |
| 专题 | 南海海洋研究所_中科院海洋生物资源可持续利用重点实验室 |
| 作者单位 | 1.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 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, South China Sea Inst Oceanol, CAS Key Lab Trop Marine Bioresources & Ecol, Guangdong Key Lab Marine Mat Med, Guangzhou 510301, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China 7.Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China 8.Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Inst Life Sci, Chongqing 400016, Peoples R China 9.Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA 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. |
| APA | Wang, Zheng.,Li, Zeng-xia.,Zhao, Wen-cao.,Huang, Hong-bo.,Wang, Jia-qi.,...&Dang, Yong-jun. |
| 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 |
入库方式： OAI收割
来源：南海海洋研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。