Characterization of the Kynurenine Pathway in Human Neurons

Guillemin, Gilles J.; Cullen, Karen M.; Lim, Chai K.; Smythe, George A.; Garner, Brett; Kapoor, Vimal; Takikawa, Osamu; Brew, Bruce J.

doi:10.1523/jneurosci.4101-07.2007

Cited by 280 publications

(302 citation statements)

References 62 publications

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“…In addition to suppressing antitumor immune responses and promoting cell survival and cell motility, trp metabolism may thus also constitute a novel metabolic mechanism to confer resistance of tumor cells to radiochemotherapy. This metabolic pathway may explain why NAD þ -depleting agents, such as FK866, are of limited efficacy in some tumors such as malignant gliomas and neuroblastomas, where quinolinic acid has been shown to be proproliferative (56,57). The resistance mechanism, as suggested by our data, seems to be regulated at the level of QPRT, which is why this enzyme may be a novel therapeutic target in malignant gliomas.…”

Section: Discussionmentioning

confidence: 71%

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

et al. 2013

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Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD þ , an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression. Here, we show that quinolinic acid accumulated in human gliomas and was associated with a malignant phenotype. Quinolinic acid was produced by microglial cells, as expression of the quinolinic acid-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) was confined to microglia in glioma tissue. Human malignant glioma cells, but not nonneoplastic astrocytes, expressed quinolinic acid phosphoribosyltransferase (QPRT) to use quinolinic acid for NAD þ synthesis and prevent apoptosis when de novo NAD þ synthesis was blocked.Oxidative stress, temozolomide, and irradiation induced QPRT in glioma cells. QPRT expression increased with malignancy. In recurrent glioblastomas after radiochemotherapy, QPRT expression was associated with a poor prognosis in two independent datasets. Our data indicate that neoplastic transformation in astrocytes is associated with a QPRT-mediated switch in NAD þ metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD þ pools. The elevated levels of QPRT expression increase resistance to oxidative stress induced by radiochemotherapy, conferring a poorer prognosis. These findings have implications for therapeutic approaches inducing intracellular NAD þ depletion, such as alkylating agents or direct NAD þ synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas. Cancer Res; 73(11); 3225-34. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 71%

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

et al. 2013

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“…Neurotoxicity would then negate these neuroprotective effects. The exact mechanism by which neuroprotection occurs is unclear, as PIC does not seem to interfere with the glutamate/NMDA binding site on the NMDA receptor (32). Thus, a highly regulated balance in the production of QUIN, PIC, and KYNA is required for normal neuronal function.…”

Section: Involvement Of the Kp In Neurotoxicitymentioning

confidence: 99%

“…Most cancer cells show a high rate of NAD þ turnover due to continuous and elevated PARP activation from DNA damage and genomic instability (73), and have significantly higher energy consumption compared with nontransformed cells (74). Interestingly, we have previously shown that ACMSD expression is absent and IDO-1 is overexpressed in the neuroblastoma cell line compared to human neurons, which express ACMSD (32). We also showed that QUIN was catabolized and PIC was produced in human neurons, whereas the neuroblastoma cell line showed a preference towards QUIN production and PIC consumption (32).…”

Section: Acmsd Dysregulation In Tumor Cells: a Speculative Role For Bmentioning

confidence: 99%

The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD þ ), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the T H 17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression. Cancer Res; 72(22); 5649-57. Ó2012 AACR.

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“…SNPs within CCBL1 and CCBL2 moderated the relationship between ADHD total, inattentive, and hyperactive-impulsive symp- tom severity. CCBL1 and CCBL2 encode kynurenine aminotransferase I and II, respectively, which transaminate kynurenine into the neuroprotective kynurenic acid [Guillemin et al, 2007;Myint et al, 2007;Vecsei et al, 2013]. Kynurenic acid is an antagonist at the N-mehtyl D-aspartic acid (NMDA) and a7 nicotinic acetylochoine (a7nACH) receptors that are implicated in learning [Hilmas et al, 2001].…”

Section: Discussionmentioning

confidence: 99%

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity

Smith

Anastopoulos

Garrett

et al. 2014

American J of Med Genetics Pt B

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Low birth weight is associated with increased risk for AttentionDeficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report.Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with

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Characterization of the Kynurenine Pathway in Human Neurons

Cited by 280 publications

References 62 publications

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

The Kynurenine Pathway in Brain Tumor Pathogenesis

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity

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