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.
Highlights
Gliomas are the most common primary central nervous system (CNS) tumor of the brain [1]
Cultures of purified human foetal astrocytes (HFA), adult astrocytes (AA) and glioma cells were immunostained with the immunocytochemical marker glial fibrillary acidic protein (GFAP) to verify the cells were of astrocytic lineage (Figure 2 (I–P))
It has been demonstrated that tryptophan degradation is induced by IFN-c in a number of cells and cell lines (SK-N-SH, neuroblastoma; T 24, J 82, bladder carcinoma; A 431, epidermoid carcinoma; normal dermal fibroblasts, U 138 MG, glioblastoma; SK-HEP-1, hepatoma; A 549, lung carcinoma; A 498, kidney carcinoma) [21]
Summary
Gliomas are the most common primary central nervous system (CNS) tumor of the brain [1]. GBM is by far, the most prevalent and most malignant type of primary brain tumor in adults [2]. GBM is an aggressive tumor that progresses rapidly, and patients with GBM have a dismal prognosis; the median survival of GBM patients is approximately 14.6 months with maximal treatment [3], but those without any intervention die soon after diagnosis [4]. This highlights the importance of developing novel pharmacological therapies with greater clinical efficacy than those that are currently available
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