title: Methionine and Kynurenine Activate Oncogenic Kinases in Glioblastoma, and Methionine Deprivation Compromises Proliferation.
abstract: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies.
  
  
  
  We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes.
  
  
  
  We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A.
  
  
  
  We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513-23. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio. Kamalakannan.palanichamy@osumc.edu.
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Palanichamy
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio. Environmental Analytical Chemistry Division, School of Advanced Sciences, VIT University, Vellore, India.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Thirumoorthy
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Suman
authors.initials: S
authors.lastname: Kanji
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Gordon
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Rajbir
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: John R
authors.initials: JR
authors.lastname: Jacob
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sebastian
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Litzenberg
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Disha
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Emily
authors.initials: E
authors.lastname: Bassett
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Brinda
authors.initials: B
authors.lastname: Ramasubramanian
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Tim
authors.initials: T
authors.lastname: Lautenschlaeger
authors.affiliation: Segment Marketing/Life Science Research, Agilent Technologies, Santa Clara, California.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Fischer
authors.affiliation: Neuropathology Unit, Surgical Neurology Branch/NINDS, NIH, Bethesda, Maryland.
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray-Chaudhury
authors.affiliation: Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D055432:Metabolomics / Q000379:methods; D008715:Methionine / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D007737:Kynurenine; D014364:Tryptophan; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase