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Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2
Author(s) -
Jiang ShuHeng,
Dong FangYuan,
Da LinTai,
Yang XiaoMei,
Wang XiaoXue,
Weng JingYi,
Feng Lei,
Zhu LiLi,
Zhang YanLi,
Zhang ZhiGang,
Sun YongWei,
Li Jun,
Xu MinJuan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901237r
Subject(s) - hexokinase , glycolysis , pancreatic cancer , cancer research , cancer , chemistry , microbiology and biotechnology , medicine , biochemistry , biology , metabolism
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.