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

Involvement of the kynurenine pathway in human glioma pathophysiology.

Author information

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.

PMID:
25415278
PMCID:
PMC4240539
DOI:
10.1371/journal.pone.0112945
[Indexed for MEDLINE]
Free PMC Article

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