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

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