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ZFIN ID: ZDB-PUB-200817-13
Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B
Wang, Z., Li, Z.X., Zhao, W.C., Huang, H.B., Wang, J.Q., Zhang, H., Lu, J.Y., Wang, R.N., Li, W., Cheng, Z., Xu, W.L., Di Zhu, ., Zhou, L.S., Jiang, W., Yu, L., Liu, J.Y., Luo, C., Zhu, H., Dan Ye, ., Pan, W.J., Ju, J.H., Dang, Y.J.
Date: 2020
Source: Acta Pharmacologica Sinica   42(5): 801-813 (Journal)
Registered Authors: Pan, Weijun
Keywords: ER stress, Zebrafish embryos, apoptosis, grincamycin B, hematological malignancies, intracellular ROS, isocitrate dehydrogenase 1, marine natural product
MeSH Terms:
  • Animals
  • Anthraquinones/metabolism
  • Anthraquinones/pharmacology*
  • Antineoplastic Agents/metabolism
  • Antineoplastic Agents/pharmacology*
  • Apoptosis/drug effects
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress/drug effects
  • Enzyme Inhibitors/metabolism
  • Enzyme Inhibitors/pharmacology*
  • Humans
  • Isocitrate Dehydrogenase/antagonists & inhibitors*
  • Isocitrate Dehydrogenase/genetics
  • Isocitrate Dehydrogenase/metabolism
  • Ketoglutaric Acids/metabolism
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Reactive Oxygen Species/metabolism
  • Zebrafish
PubMed: 32796956 Full text @ Acta Pharmacol. Sin.
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.
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