Evidence for Increased de Novo Synthesis of NAD in Immune-Activated RAW264.7 Macrophages: A Self-Protective Mechanism?

Grant, Ross; Passey, Robert; Matanovic, Gabrijela; Smythe, George A.; Kapoor, Vimal

doi:10.1006/abbi.1999.1381

Cited by 63 publications

(60 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, tryptophan catabolism appears in principle capable of replenishing depleted intracellular NAD þ stores and protecting cells from oxidative stress as evidenced by in vitro studies (48)(49)(50)(51). These studies also showed that nicotinic acid is a preferred route of NAD þ synthesis in murine astrocytes in line with our findings in human cells and tissue (50).…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…While our data do not show a direct cause and effect relationship between IDO activity and oxidative damage, our results are consistent with the postulate that IDO activity may have an antioxidant function [11,[25][26][27]. IDO activity could mitigate oxidative damage by multiple mechanisms: (1) consuming superoxide anions [68,69], which should limit the formation of other ROS; (2) generating downstream products, including 3-hydroxykynurenine and 3-hydroxyanthranilic acid, which are free radical scavengers [11,26,70,71]; (3) increasing cellular NAD levels, which indirectly helps to maintain cell viability [72,73]. RAW 264.7 macrophages probably possess the enzymes required make 3-hydroxykynurenine, 3-hydroxyanthranilic acid and NAD [73,74]; therefore, we cannot dismiss the potential contribution of those molecules to the apparent antioxidant effect of IDO.…”

Section: Discussionsupporting

confidence: 76%

“…IDO activity could mitigate oxidative damage by multiple mechanisms: (1) consuming superoxide anions [68,69], which should limit the formation of other ROS; (2) generating downstream products, including 3-hydroxykynurenine and 3-hydroxyanthranilic acid, which are free radical scavengers [11,26,70,71]; (3) increasing cellular NAD levels, which indirectly helps to maintain cell viability [72,73]. RAW 264.7 macrophages probably possess the enzymes required make 3-hydroxykynurenine, 3-hydroxyanthranilic acid and NAD [73,74]; therefore, we cannot dismiss the potential contribution of those molecules to the apparent antioxidant effect of IDO. Activated macrophages are a major source of superoxide anions [75][76][77]; it is possible that macrophage IDO activity curbs superoxide anion production, thereby minimizing oxidative damage to macrophages and nearby cells.…”

Section: Discussionmentioning

confidence: 99%

Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase

Keskin

Marshall

Munn

et al. 2007

Cellular and Molecular Biology Letters

View full text Add to dashboard Cite

Abstract:The activity of indoleamine 2, 3-dioxygenase (IDO; E.C. 1.13.11.42) catalyzes the oxidative cleavage of tryptophan to form kynurenine. IDO activity consumes superoxide anions; therefore, we postulated that over-expression of IDO might mitigate superoxide-anion dependent, oxidative modification of cellular proteins in vitro. We prepared and characterized RAW 264.7 macrophages that were stably transfected with either an IDO expression vector or the control (empty) vector. We detected IDO mRNA, protein, and enzyme activity in the IDO-transfected macrophages, but not in the macrophages transfected with the empty vector. To generate superoxide anions in situ, we treated the IDO-and control-transfected cultures with xanthine or hypoxanthine, and then used ELISA methods to quantitate the relative levels of oxidatively modified proteins in total cell lysates. The levels of protein carbonyls were similar in IDO-transfected and vector-transfected macrophages; however, protein nitration was significantly less in IDO-transfected cells compared to control transfectants. In addition, steady-state levels of superoxide anions were significantly lower in the IDO-transfected cultures compared with control transfectants. Our results are consistent with the concept that, besides degrading tryptophan, IDO activity may protect cells from oxidative damage.

show abstract

“…Bna4 and Bna5 catalyze the ensuing conversion to 3-hydroxykynurenine and 3-hydroxyanthanilic acid, respectively. An oxidoreductase encoded by BNA1 then catalyzes the formation of quinolinic acid, which is converted into NaMN by the BNA6 gene product (also known as QPT1) (56,165). It is interesting that the de novo pathway for NAD ϩ synthesis does not appear to be essential for either Sir2-dependent silencing or life span extension by calorie restriction.…”

Section: Vol 67 2003 Aging In Saccharomyces Cerevisiae 387mentioning

confidence: 99%

Longevity Regulation inSaccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin

Bitterman

Medvedik

Sinclair

2003

Microbiol Mol Biol Rev

214

152

View full text Add to dashboard Cite

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae

show abstract

Evidence for Increased de Novo Synthesis of NAD in Immune-Activated RAW264.7 Macrophages: A Self-Protective Mechanism?

Cited by 63 publications

References 31 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

Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase

Longevity Regulation inSaccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin

Contact Info

Product

Resources

About