Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

Mangrove‐derived actinobacteria strains are well‐known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro....

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Bibliographic Details
Published in:The FASEB journal 2020-03, Vol.34 (3), p.3943-3955
Main Authors: Jiang, Shu‐Heng, Dong, Fang‐Yuan, Da, Lin‐Tai, Yang, Xiao‐Mei, Wang, Xiao‐Xue, Weng, Jing‐Yi, Feng, Lei, Zhu, Li‐Li, Zhang, Yan‐Li, Zhang, Zhi‐Gang, Sun, Yong‐Wei, Li, Jun, Xu, Min‐Juan
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Survival - drug effects
chemosensitivity
Glucose - metabolism
Glycolysis - drug effects
hexokinase
Hexokinase - metabolism
Humans
Immunohistochemistry
Lactams - pharmacology
Lactic Acid - metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
pancreatic cancer
Real-Time Polymerase Chain Reaction
Streptomyces
Surface Plasmon Resonance
Warburg effect
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Summary:Mangrove‐derived actinobacteria strains are well‐known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome‐based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose‐6‐phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201901237R