UCSF

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), and the excitotoxic neurotoxin, quinolinic acid (QUIN). 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. Downstream enzymes include kynureninase (KYNU), 3-hydroxyanthranilate 3,4-dioxygenase (3-HAAO), kynurenine hydroxylase (KMO) and 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD). Kynurenine aminotransferase-I (KAT-I) is one of the enzymes responsible for synthesising KYNA. Mounting evidence directly implicates that IDO-1 induction in various tumours is a crucial mechanism facilitating tumour immune evasion and persistence. However, the involvement of the downstream machinery of the KP in brain tumour progression remains unexplored. A complete characterisation of the KP in brain tumours and the role of the KP in maintaining homeostasis between neuroprotection and neurodegeneration in glioma has not yet been investigated. Here we report the first comprehensive characterisation of the KP in cultured human glioma cells and GBM patient plasma. Our qRT-PCR data revealed that interferon-gamma (IFN-γ) (100 IU/ml) stimulation significantly potentiated the expression of IDO-1 IDO-2, KYNU, 3-HAAO, KMO and significantly down-regulated ACMSD and KAT-I expression in cultured human glioma cells. HPLC analysis revealed that IFN-γ stimulation significantly increased KP activity (KYN/TRP ratio), and significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. Our HPLC and GCMS data revealed that KP activation was significantly higher and the concentrations of 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 highlights a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumours.