Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas

Bostian, April C.L.; Eoff, Robert L.

doi:10.1021/acs.chemrestox.6b00255

Cited by 11 publications

(7 citation statements)

References 143 publications

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“…The dysregulation of the kynurenine pathway in cancer may also promote malignancy by NAD+ production, which could directly affect several cellular functions. Furthermore, NAD+ can activate the transcription factor aryl hydrocarbon receptor (AhR) and consequently regulate gene expression (Bostian and Eoff 2016).…”

Section: Kynurenine Pathway In Cancermentioning

confidence: 99%

Inflammation in cancer and depression: a starring role for the kynurenine pathway

et al. 2019

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Depression is a common comorbidity in cancer cases, but this is not only due to the emotional distress of having a life-threatening disease. A common biological mechanism, involving a dysregulated immune system, seems to underpin this comorbidity. In particular, the activation of the kynurenine pathway of tryptophan degradation due to inflammation may play a key role in the development and persistence of both diseases. As a consequence, targeting enzymes involved in this pathway offers a unique opportunity to develop new strategies to treat cancer and depression at once. In this work, we provide a systematic review of the evidence up to date on the kynurenine pathway role in linking depression and cancer and on clinical implications of this evidence. In particular, complications due to chemotherapy are discussed, as well as the potential antidepressant efficacy of novel immunotherapies for cancer.Electronic supplementary materialThe online version of this article (10.1007/s00213-019-05200-8) contains supplementary material, which is available to authorized users.

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Section: Kynurenine Pathway In Cancermentioning

confidence: 99%

Inflammation in cancer and depression: a starring role for the kynurenine pathway

et al. 2019

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“…In mammalian, QUIN has been shown to increase the production of free radicals, leading to oxidative stress, DNA damage, and increased poly(ADP-ribose) polymerase 1 (PARP-1) activity 57 , 58 . However, moderate QUIN level can induce resistance to oxidative stress through increased NAD + production 59 . NAD + influences DNA repair and gene expression through its role as a substrate for PARP-1 in mammal cells.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the GAPDH gene contributes to genome stability in Saccharomyces cerevisiae

Hanasaki

Yaku

Yamauchi

et al. 2020

Sci Rep

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Cellular metabolism is directly or indirectly associated with various cellular processes by producing a variety of metabolites. Metabolic alterations may cause adverse effects on cell viability. However, some alterations potentiate the rescue of the malfunction of the cell system. Here, we found that the alteration of glucose metabolism suppressed genome instability caused by the impairment of chromatin structure. Deletion of the TDH2 gene, which encodes glyceraldehyde 3-phospho dehydrogenase and is essential for glycolysis/gluconeogenesis, partially suppressed DNA damage sensitivity due to chromatin structure, which was persistently acetylated histone H3 on lysine 56 in cells with deletions of both HST3 and HST4, encoding NAD+-dependent deacetylases. tdh2 deletion also restored the short replicative lifespan of cells with deletion of sir2, another NAD+-dependent deacetylase, by suppressing intrachromosomal recombination in rDNA repeats increased by the unacetylated histone H4 on lysine 16. tdh2 deletion also suppressed recombination between direct repeats in hst3∆ hst4∆ cells by suppressing the replication fork instability that leads to both DNA deletions among repeats. We focused on quinolinic acid (QUIN), a metabolic intermediate in the de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway, which accumulated in the tdh2 deletion cells and was a candidate metabolite to suppress DNA replication fork instability. Deletion of QPT1, quinolinate phosphoribosyl transferase, elevated intracellular QUIN levels and partially suppressed the DNA damage sensitivity of hst3∆ hst4∆ cells as well as tdh2∆ cells. qpt1 deletion restored the short replicative lifespan of sir2∆ cells by suppressing intrachromosomal recombination among rDNA repeats. In addition, qpt1 deletion could suppress replication fork slippage between direct repeats. These findings suggest a connection between glucose metabolism and genomic stability.

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“…Indeed, TDO2 or AhR inactivation, similarly to the hpol k knock-down, reduces chromosomal instability in glioma cell lines, as assessed by micronuclei formation [ 84 ]. Combining TDO2 or AhR inhibitors with temozolomide has thus been proposed as an appealing alternative treatment for glioma patients [ 85 ].…”

Section: Consequences Of the Activation Of The First Immunosuppressiv...mentioning

confidence: 99%

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

Gouasmi

Ferraro‐Peyret

Nancey

et al. 2022

Cancers

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The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success.

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Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas

Cited by 11 publications

References 143 publications

Inflammation in cancer and depression: a starring role for the kynurenine pathway

Inflammation in cancer and depression: a starring role for the kynurenine pathway

Deletion of the GAPDH gene contributes to genome stability in Saccharomyces cerevisiae

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

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