Involvement of the kynurenine pathway in human glioma pathophysiology

Seray Adams, Charles Teo, Kerrie L. McDonald, Anna Zinger, Sonia Bustamante, Chai K. Lim, Gayathri Sundaram, Nady Braidy, Bruce J. Brew, Gilles J. Guillemin

    Research output: Contribution to journalArticleResearchpeer-review

    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 (n518) 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.

    LanguageEnglish
    Article number0112945
    Pages1-28
    Number of pages28
    JournalPLoS ONE
    Volume9
    Issue number11
    DOIs
    Publication statusPublished - 17 Oct 2014

    Fingerprint

    Kynurenine
    pathophysiology
    kynurenine
    Glioma
    Indoleamine-Pyrrole 2,3,-Dioxygenase
    Kynurenic Acid
    NAD (coenzyme)
    acids
    picolinic acid
    tryptophan
    neoplasms
    Tumors
    Tryptophan
    NAD
    Quinolinic Acid
    kynurenine-oxoglutarate transaminase
    immunity
    tryptophan 2,3-dioxygenase
    Glioblastoma
    kynureninase

    Bibliographical note

    Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

    Cite this

    Adams, Seray ; Teo, Charles ; McDonald, Kerrie L. ; Zinger, Anna ; Bustamante, Sonia ; Lim, Chai K. ; Sundaram, Gayathri ; Braidy, Nady ; Brew, Bruce J. ; Guillemin, Gilles J. / Involvement of the kynurenine pathway in human glioma pathophysiology. In: PLoS ONE. 2014 ; Vol. 9, No. 11. pp. 1-28.
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    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 (n518) 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.",
    author = "Seray Adams and Charles Teo and McDonald, {Kerrie L.} and Anna Zinger and Sonia Bustamante and Lim, {Chai K.} and Gayathri Sundaram and Nady Braidy and Brew, {Bruce J.} and Guillemin, {Gilles J.}",
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    Adams, S, Teo, C, McDonald, KL, Zinger, A, Bustamante, S, Lim, CK, Sundaram, G, Braidy, N, Brew, BJ & Guillemin, GJ 2014, 'Involvement of the kynurenine pathway in human glioma pathophysiology', PLoS ONE, vol. 9, no. 11, 0112945, pp. 1-28. https://doi.org/10.1371/journal.pone.0112945

    Involvement of the kynurenine pathway in human glioma pathophysiology. / Adams, Seray; Teo, Charles; McDonald, Kerrie L.; Zinger, Anna; Bustamante, Sonia; Lim, Chai K.; Sundaram, Gayathri; Braidy, Nady; Brew, Bruce J.; Guillemin, Gilles J.

    In: PLoS ONE, Vol. 9, No. 11, 0112945, 17.10.2014, p. 1-28.

    Research output: Contribution to journalArticleResearchpeer-review

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    AU - Teo, Charles

    AU - McDonald, Kerrie L.

    AU - Zinger, Anna

    AU - Bustamante, Sonia

    AU - Lim, Chai K.

    AU - Sundaram, Gayathri

    AU - Braidy, Nady

    AU - Brew, Bruce J.

    AU - Guillemin, Gilles J.

    N1 - Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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