&lt;b&gt;Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluor&lt;/b&gt;&lt;b&gt;ouracil &lt;/b&gt;

Hozumi, Yasukazu; Tanaka, Toshiaki; Nakano, Tomoyuki; Matsui, Hiroki; Nasu, Takashi; Koike, Shuji; Kakehata, Seiji; Ito, Tsukasa; Goto, Kaoru

doi:10.2220/biomedres.36.403

Cited by 4 publications

(1 citation statement)

References 15 publications

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“…Interestingly, TP has also been reported as a driver of tumour proliferation and metastasis [ 289 ], illustrating that nucleoside analogue metabolising enzymes can be double-edged swords, as reported for SAMHD1 [ 118 ]. In a 5-FU resistant cell line, UMPS down-regulation was identified [ 135 ], whereas experimental overexpression of UMPS increased toxicity of 5-FU in vitro [ 290 , 291 ], and the ratio of UMPS-to-DPD expression has been associated with better overall survival in a Japanese cohort of 5-FU-treated patients with colorectal cancer [ 292 ]. High UMPS expression was confirmed to correlate with patient survival in another colorectal cancer cohort [ 293 ] as well as in patients with oesophageal squamous cell carcinoma [ 294 ].…”

Section: Tumour-specific Resistance To Nucleobase/nucleoside Analomentioning

confidence: 99%

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Tsesmetzis

Paulin

Rudd

et al. 2018

Cancers

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Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.

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Section: Tumour-specific Resistance To Nucleobase/nucleoside Analomentioning

confidence: 99%

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Tsesmetzis

Paulin

Rudd

et al. 2018

Cancers

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Diacylglycerol kinase ε localizes to subsurface cisterns of cerebellar Purkinje cells

et al. 2017

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Following activation of Gq protein-coupled receptors, phospholipase C yields a pair of second messengers: diacylglycerol (DG) and inositol 1,4,5-trisphosphate. Diacylglycerol kinase (DGK) phosphorylates DG to produce phosphatidic acid, another second messenger. Of the DGK family, DGKε is the only DGK isoform that exhibits substrate specificity for DG with an arachidonoyl acyl chain at the sn-2 position. Recently, we demonstrated that hydrophobic residues in the N-terminus of DGKε play an important role in targeting the endoplasmic reticulum in transfected cells. However, its cellular expression and subcellular localization in the brain remain elusive. In the present study, we investigate this issue using specific DGKε antibody. DGKε was richly expressed in principal neurons of higher brain regions, including pyramidal cells in the hippocampus and neocortex, medium spiny neurons in the striatum and Purkinje cells in the cerebellum. In Purkinje cells, DGKε was localized to the subsurface cisterns and colocalized with inositol 1,4,5-trisphosphate receptor-1 in dendrites and axons. In dendrites of Purkinje cells, DGKε was also distributed in close apposition to DG lipase-α, which catalyzes arachidonoyl-DG to produce 2-arachidonoyl glycerol, a major endocannabinoid in the brain. Behaviorally, DGKε-knockout mice exhibited hyper-locomotive activities and impaired motor coordination and learning. These findings suggest that DGKε plays an important role in neuronal and brain functions through its distinct neuronal expression and subcellular localization and also through coordinated arrangement with other molecules involving the phosphoinositide signaling pathway.

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Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis

et al. 2022

J Physiol Biochem

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<b>Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluor</b><b>ouracil </b>

Cited by 4 publications

References 15 publications

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Diacylglycerol kinase ε localizes to subsurface cisterns of cerebellar Purkinje cells

Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis

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