title: 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(+), 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(+) synthesis and prevent apoptosis when de novo NAD(+) 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(+) metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD(+) 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(+) depletion, such as alkylating agents or direct NAD(+) synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas.
authors.affiliation: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Frankfurt, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.forename: Iris
authors.initials: I
authors.lastname: Oezen
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Tilman
authors.initials: T
authors.lastname: Ahrendt
authors.forename: Seray
authors.initials: S
authors.lastname: Adams
authors.forename: Helge B
authors.initials: HB
authors.lastname: Bode
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017628:Microglia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010430:Pentosyltransferases / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism*; D000077204:Temozolomide; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009243:NAD; D003606:Dacarbazine; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D017378:Quinolinic Acid; D000077204:Temozolomide