Involvement of the kynurenine pathway in human glioma pathophysiology

Seray Adams; Charles Teo; Kerrie L McDonald; Anna Zinger; Sonia Bustamante; Chai K Lim; Gayathri Sundaram; Nady Braidy; Bruce J Brew; Gilles J Guillemin

doi:10.1371/journal.pone.0112945

Involvement of the kynurenine pathway in human glioma pathophysiology

PLoS One. 2014 Nov 21;9(11):e112945. doi: 10.1371/journal.pone.0112945. eCollection 2014.

Authors

Affiliations

¹ MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
² Centre for Minimally Invasive Neurosurgery, Prince of Wales Hospital, Sydney, NSW, Australia.
³ Cure For Life Neuro-Oncology Group, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
⁴ School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
⁵ Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia.
⁶ St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia.
⁷ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁸ St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia; Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia.
⁹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
Astrocytes / drug effects
Astrocytes / metabolism
Biosynthetic Pathways*
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Brain Neoplasms / physiopathology
CD11b Antigen / metabolism
Carboxy-Lyases / genetics
Carboxy-Lyases / metabolism
Cells, Cultured
Chromatography, High Pressure Liquid
Disaccharides
Gene Expression / drug effects
Glial Fibrillary Acidic Protein / metabolism
Glioma / genetics
Glioma / metabolism*
Glioma / physiopathology
Glucuronates
Humans
Immunohistochemistry
Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Interferon-gamma / pharmacology
Kynurenic Acid / blood
Kynurenic Acid / metabolism
Kynurenine / biosynthesis*
Kynurenine / blood
Picolinic Acids / blood
Picolinic Acids / metabolism
Quinolinic Acid / blood
Quinolinic Acid / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tryptophan / blood
Tryptophan / metabolism
Tryptophan Oxygenase / genetics
Tryptophan Oxygenase / metabolism
Tumor Cells, Cultured

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD11b Antigen
CD68 antigen, human
Disaccharides
Glial Fibrillary Acidic Protein
Glucuronates
Indoleamine-Pyrrole 2,3,-Dioxygenase
Picolinic Acids
Kynurenine
Interferon-gamma
Tryptophan
O-(glucuronic acid 2-sulfate)-(1--4)-O-(2,5)-anhydromannitol 6-sulfate
Tryptophan Oxygenase
Carboxy-Lyases
aminocarboxymuconate-semialdehyde decarboxylase
Quinolinic Acid
Kynurenic Acid
picolinic acid

Grants and funding

This work has been supported by the Tour de Cure (Cure for Life Foundation), the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC), the Peter Duncan Foundation, and the Curran Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.