The involvement of the kynurenine pathway in brain tumour pathogenesis

Abstract

Glioblastoma multiforme (GBM) is the most prevalent type of primary brain tumour in adults and the prognosis for patients remains dismal. 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 neurotoxin, quinolinic acid (QUIN) and quinaldic acid (QA). 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. Mounting evidence directly implicates that the induction of IDO-1 in various tumours is a crucial mechanism facilitating tumour immune evasion and persistence. TDO-2 has recently been shown to be a mechanism of tumoural immune resistance. However, the involvement of the downstream machinery of the KP in brain tumour progression has been virtually unexplored. Further, a full characterisation of the KP in brain tumours and the role of the KP in terms of the balance between neuroprotection and neurodegeneration in GBM has not yet been investigated. Here we report the first comprehensive characterisation of the KP in human primary GBM in vitro and in vivo. qRT-PCR revealed that IFN-γ stimulation significantly potentiated the expression of IDO-1 and IDO-2 in GBM cells. HPLC analysis revealed that IFN-γ stimulation significantly increased KP activity (KYN/TRP ratio) and significantly lowered the KYNA/KYN neuroprotective ratio in GBM cells. Using both HPLC and GC/MS, it was revealed that KP activation (KYN/TRP) and QA production was shown to be significantly higher and the concentrations of TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were shown to be significantly lower in GBM patient plasma (n=18) compared to controls. In conclusion, this study has confirmed that the KP is up-regulated and that both neuroprotective branches of the KP are impaired in GBM patients. These results provide strong evidence which implicates the involvement of the KP in GBM pathophysiology and highlights that pharmacological approaches aimed at restoring the physiological balance of these imbalanced metabolites and augmented enzymes may be promising novel therapeutic targets for the treatment of brain cancer.