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Involvement of the kynurenine pathway in human glioma pathophysiology.
- Source :
-
PloS one [PLoS One] 2014 Nov 21; Vol. 9 (11), pp. e112945. Date of Electronic Publication: 2014 Nov 21 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Antigens, CD metabolism
Antigens, Differentiation, Myelomonocytic metabolism
Astrocytes drug effects
Astrocytes metabolism
Brain Neoplasms genetics
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 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 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
Biosynthetic Pathways
Brain Neoplasms metabolism
Glioma metabolism
Kynurenine biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25415278
- Full Text :
- https://doi.org/10.1371/journal.pone.0112945