Targeting nuclear thymidylate biosynthesis

Chon, James W. M.; Stover, Patrick J.; Field, Martha S.

doi:10.1016/j.mam.2016.11.005

Cited by 55 publications

(57 citation statements)

References 121 publications

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“…Besides its role as a methyl group donor for the remethylation of homocysteine, CH 2 THF is also a source of methyl groups for the synthesis of thymidylate or deoxythimidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP). The net effect of reduced CH 2 THF may be impaired de novo dTMP synthesis and a greater rate of uracil misincorporation into DNA, resulting in single-and double-stranded breaks through the actions of DNA repair enzymes [60]. Our findings assume importance given previous studies implicating genome instability and impaired DNA repair in AD pathogenesis [61].…”

Section: Genementioning

confidence: 60%

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

et al. 2020

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Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's

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Section: Genementioning

confidence: 60%

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

et al. 2020

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“…Rather, it reveals a specific characteristic of cisplatin-resistant cells that be taken advantage of to kill them. More importantly from the therapeutic point of view, we observed that CDDP-resistant cells acquired an exquisite susceptibility to several chemotherapeutic agents that inhibit nucleotide metabolism such as 5-fluorouracil (5-FU, an inhibitor of thymidylate synthase; Chon et al, 2017) or clofarabine (CLO, an inhibitor of ribonucleotide reductase; Aye et al, 2015). Interestingly, a recent siRNA-based genetic screen also revealed that knockdown of ribonucleoside-diphosphate reductase subunit M2 B can sensitize cancer cells to CDDP as well (Leung et al, 2016), pleading in favor of the specificity of the effects.…”

Section: Discussionmentioning

confidence: 99%

Metabolic vulnerability of cisplatin‐resistant cancers

et al. 2018

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Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation and than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.

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“…3 5-fluorouracil (5-FU) is currently a first-line agent for the clinical treatment of GC, which affects the de novo synthesis of DNA by multiple mechanisms, such as incorporation into RNA or DNA, and suppression of thymidine synthase, resulting in cell death. 4 Despite their overall efficacy, GC cells often develop resistance to 5-FU. Thus, novel strategies to overcome the resistance of GC cells to 5-FU are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

<p>Circular RNA circNRIP1 Sponges microRNA-138-5p to Maintain Hypoxia-Induced Resistance to 5-Fluorouracil Through HIF-1α-Dependent Glucose Metabolism in Gastric Carcinoma</p>

et al. 2020

CMAR

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Background: Hypoxia-induced chemoresistance is recognized as a major obstacle to the successful treatment of gastric cancer (GC). Circular RNAs (circRNAs) have been proposed to implicate in resistance to chemotherapeutic drugs. However, whether circNRIP1 is involved in the development of hypoxia-induced 5-fluorouracil (5-FU) resistance remains largely unknown. Methods: Gene expression was evaluated using quantitative real-time polymerase chain reaction and Western blot. The impact of circNRIP1 on hypoxia-induced resistance to 5-FU was investigated by determining glucose consumption, lactate production and glucose-6-phosphate (G6P) levels. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide assay was performed to assess cell survival. Results: circNRIP1 was upregulated in GC cells. Hypoxia induced the upregulation of circNRIP1 and reduced the sensitivity of GC cells to 5-FU, as evidenced by the increase in multidrug resistance 1 gene, P-glycoprotein, hypoxia-inducible factor-1α (HIF-1α) and G6P levels, glucose consumption, lactate production, as well as cell survival. Silencing of circNRIP1 enhanced the sensitivity of GC cells to 5-FU under a hypoxic condition. microRNA (miR)-138-5p was confirmed as a downstream target gene of circNRIP1, and upregulation of miR-138-5p could reverse the effect of circNRIP1 on hypoxia-induced 5-FU resistance. Additionally, HIF-1α was a target gene of miR-138-5p. More significantly, the effect of circNRIP1 on hypoxia-induced 5-FU resistance was markedly blocked by 2-DG treatment. Conclusion: circNRIP1 functioned as a miR-138-5p sponge to enhance hypoxia-induced resistance to 5-FU through modulation of HIF-1α-dependent glycolysis, which provides a novel potential approach to overcome hypoxia-induced 5-FU resistance in GC.

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Targeting nuclear thymidylate biosynthesis

Cited by 55 publications

References 121 publications

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

Metabolic vulnerability of cisplatin‐resistant cancers

<p>Circular RNA circNRIP1 Sponges microRNA-138-5p to Maintain Hypoxia-Induced Resistance to 5-Fluorouracil Through HIF-1α-Dependent Glucose Metabolism in Gastric Carcinoma</p>

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