Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival

Liang, Jin; Wang, Chong; Yiu, Stephanie Pei Tung; Guo, Rui; Gewurz, Benjamin E.

doi:10.1128/mbio.01530-21

Cited by 21 publications

(24 citation statements)

References 55 publications

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“…EBV also up-regulates the isozyme CTPS2, which plays a partially redundant role with CTPS1 in EBV-transformed B cells. Interestingly, Burkitt and lymphoblastoid cells can utilize cytidine salvage metabolism, in which imported uridine or cytidine are converted to CTP [ 29 ]. This plasticity may underlie the clinical observation that EBV+ lymphomas frequently occur in patients with inborn hypomorphic CTPS1 mutations that severely impair T/NK cell immunity [ 30 ].…”

Section: Ebv-driven Purine and Pyrimidine Nucleotide Metabolismmentioning

confidence: 99%

Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Burton

Gewurz

2022

PLoS Pathog

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Section: Ebv-driven Purine and Pyrimidine Nucleotide Metabolismmentioning

confidence: 99%

Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Burton

Gewurz

2022

PLoS Pathog

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“…Similarly, the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) generates CoQH 2, which can be used to quench lipid ROS within the mitochondrial inner membrane ( 54 ). We recently identified that EBV highly induces DHODH and de novo pyrimidine activity in newly infected B cells ( 55 ). Furthermore, GTP cyclohydrolase 1 (GCH1) can suppress ferroptosis via the generation of the radical-trapping antioxidant tetrahydrobiopterin (BH4) ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus latency programs dynamically sensitize B cells to ferroptosis

Burton

Voyer

Gewurz

2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Epstein–Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas.

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“…So far, no defined upstream factors have been reported to induce UCK2 expression in tumor. However, some previous studies do have indicated that the aberrant overexpression of UCK2 might be attributed to the gene amplication of UCK2 ( 27 ), the infection of Epstein–Barr virus ( 38 ), the m 6 A modification induced by METTL3 ( 39 ), hypoxia ( 40 ), and downregulation of certain miRNAs ( 46 ). Moreover, functional studies have demonstrated that overexpression of UCK2 can promote cell proliferation and migration in lung cancer and HCCs ( 20 , 27 ).…”

Section: Role Of Uck2 In Tumor Developmentmentioning

confidence: 99%

The Metabolic and Non-Metabolic Roles of UCK2 in Tumor Progression

Wei

Guo

et al. 2022

Front. Oncol.

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Enhanced nucleoside metabolism is one of the hallmarks of cancer. Uridine-cytidine kinase 2 (UCK2) is a rate-limiting enzyme of the pyrimidine salvage synthesis pathway to phosphorylate uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. Recent studies have shown that UCK2 is overexpressed in many types of solid and hematopoietic cancers, closely associates with poor prognosis, and promotes cell proliferation and migration in lung cancer and HCCs. Although UCK2 is thought to catalyze sufficient nucleotide building blocks to support the rapid proliferation of tumor cells, we and other groups have recently demonstrated that UCK2 may play a tumor-promoting role in a catalytic independent manner by activating oncogenic signaling pathways, such as STAT3 and EGFR-AKT. By harnessing the catalytic activity of UCK2, several cytotoxic ribonucleoside analogs, such as TAS-106 and RX-3117, have been developed for UCK2-mediated cancer chemotherapy. Moreover, we have demonstrated that the concurrent targeting of the catalytic dependent and independent features of UCK2 could synergistically inhibit tumor growth. These findings suggest that UCK2 may serve as a potential therapeutic target for cancer treatment. In this mini-review, we introduced the genomic localization and protein structure of UCK2, described the role of UCK2 in tumor development, discussed the application of UCK2 in anti-tumor treatment, and proposed concurrent targeting of the catalytic and non-catalytic roles of UCK2 as a potential therapeutic strategy for cancer treatment.

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Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival

Cited by 21 publications

References 55 publications

Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Epstein–Barr virus latency programs dynamically sensitize B cells to ferroptosis

The Metabolic and Non-Metabolic Roles of UCK2 in Tumor Progression

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