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

Abstract

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.

Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

“…Both deacetylation catalyzed by sirtuins and ADP-ribosylation are NAD+ consuming processes (19,20,21), making cells dependent on NAD+ synthesis through the salvage pathway and through the de novo pathway, in which QPRT plays a key role. In line with this, QPRT was reported to increase resistance of glioma brain cancer cells to radiation and oxidative stress, by activating an NAD+ salvage pathway (22).…”

“…In a study on QPRT in glioma brain cancer cells, QPRT was found to increase resistance to radiation and oxidative stress (22). QPRT expression increases with a higher degree of malignancy in glioblastoma and levels of QPRT correlated to an unfavorable prognosis (22).…”

“…In a study on QPRT in glioma brain cancer cells, QPRT was found to increase resistance to radiation and oxidative stress (22). QPRT expression increases with a higher degree of malignancy in glioblastoma and levels of QPRT correlated to an unfavorable prognosis (22). Interestingly, also WT1 expression correlates to malignancy (42) and glioma cell lines revealed an increased sensitivity of tumor cells to radiation treatment as a result of WT1 knock-down (43).…”

“…QPRT has been reported to have anti-apoptotic properties (22). K562 cells are dependent on the BCR-ABL1 oncogene, and thus sensitive to the clinically used tyrosine kinase inhibitor imatinib (40).…”

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

“…Many of the chromatin-modifying enzymes involved in DNA repair depend on metabolic intermediates as cofactors for their activity, thereby directly linking changes in cellular metabolism with DNA repair (30). Interestingly, high levels of NAD + (nicotinamide adenine dinucleotide) correlate with radioprotection of human glioma cells (31). Alterations in NAD + levels modulate DNA repair and NAD + is elevated under conditions of nutrient deprivation.…”