title: Metabolomics study on the antitumor effect of marine natural compound flexibilide in HCT-116 colon cancer cell line.
abstract: A marine natural compound flexibilide isolated from the soft coral Sinularia flexibilis has been found to have antitumor activity. However, its pharmacological mechanism on tumor cells has not been studied. Herein, an ultra-performance liquid chromatography coupled to quadrupole time of-flight mass spectrometry (UPLC/Q-TOF MS) based metabolomics approach was established to investigate the antitumor effect of flexibilide on HCT-116 cells and its action mechanism. Q-TOF MS and MS/MS were used to identify significantly different metabolites. Comparing flexibilide-treated HCT-116 cells group with control group (dimethyl sulfoxide), 19 distinct metabolites involved in sphingolipid metabolism, alanine, aspartate and glutamate metabolism, d-glutamine and d-glutamate metabolism, glycerophospholipid metabolism, pyrimidine metabolism and others were discovered and identified. The significant decrease of phosphatidylcholine (PC) and phosphocholine levels and increase of lysophosphatidylcholine (LysoPC) levels in flexibilide treated cells suggested down-regulation of PC biosynthesis pathway. The decrease of sphingolipids reflected the lesions of cell membrane, and the up-regulation of sphingosine-1-phosphate indicated that TRAF2 and caspase-8 were likely to be activated by flexibilide and further caused cell apoptosis. Furthermore, TCA cycle was deemed to be down-regulated after flexibilide treatment, which might lead to an unsustainable of mitochondrial transmembrane potential MMP). The further measured descreased MMP with the increasing concentration of flexibilide treatment indiciated the dysfunction of mitochondrial which might finally lead to apoptosis. The UPLC/Q-TOF MS based metabolomics approach provides new insights into the mechanistic studies of flexibilide on tumor cells, which benefit its further improvement and application.
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors: Dan
authors: D
authors: Gao
authors: Department of Chemistry, Tsinghua University, Beijing 100084, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors: Yini
authors: Y
authors: Wang
authors: Department of Chemistry, Tsinghua University, Beijing 100084, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors: Weiyi
authors: W
authors: Xie
authors: Department of Chemistry, Tsinghua University, Beijing 100084, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors: Ti
authors: T
authors: Yang
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Yuyang
authors: Y
authors: Jiang
authors: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yuewei
authors: Y
authors: Guo
authors: School of Applied Chemistry, Shenyang Chemical Technology University, Shenyang 110142, China. Electronic address: guanj0418@163.com.
authors: Jin
authors: J
authors: Guan
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China. Electronic address: liuhx@sz.tsinghua.edu.cn.
authors: Hongxia
authors: H
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000187:drug effects* / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D010713:Phosphatidylcholines; D010767:Phosphorylcholine / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D007783:Lactones; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D010767:Phosphorylcholine; C060506:sphingosine 1-phosphate; C027469:flexibilide; D013110:Sphingosine
keywords: Action mechanism; Flexibilide; HCT-116 cells; Metabolomics; UPLC/Q-TOF MS