title: Involvement of the kynurenine pathway in human glioma pathophysiology.
abstract: The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+), which is necessary for energy production and DNA repair.
authors.affiliation: MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Seray
authors.initials: S
authors.lastname: Adams
authors.affiliation: Centre for Minimally Invasive Neurosurgery, Prince of Wales Hospital, Sydney, NSW, Australia.
authors.forename: Charles
authors.initials: C
authors.lastname: Teo
authors.affiliation: Cure For Life Neuro-Oncology Group, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
authors.affiliation: School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Zinger
authors.affiliation: Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bustamante
authors.affiliation: MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Chai K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Sundaram
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.affiliation: St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia; Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Brew
authors.affiliation: MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia; St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia; Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D053898:Biosynthetic Pathways; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D039481:CD11b Antigen / Q000378:metabolism; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004187:Disaccharides; D015870:Gene Expression / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005965:Glucuronates; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism; D007737:Kynurenine / Q000096:biosynthesis* / Q000097:blood; D010848:Picolinic Acids / Q000097:blood / Q000378:metabolism; D017378:Quinolinic Acid / Q000097:blood / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014364:Tryptophan / Q000097:blood / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D002262:Carboxy-Lyases; D004187:Disaccharides; D005904:Glial Fibrillary Acidic Protein; D005965:Glucuronates; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D007736:Kynurenic Acid; D007737:Kynurenine; D010848:Picolinic Acids; D017378:Quinolinic Acid; D014364:Tryptophan; D014366:Tryptophan Oxygenase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C059554:O-(glucuronic acid 2-sulfate)-(1--4)-O-(2,5)-anhydromannitol 6-sulfate; C024396:aminocarboxymuconate-semialdehyde decarboxylase; C030614:picolinic acid