气候变化领域集成服务门户(CCPortal): Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas

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DOI	10.1073/pnas.2022495118
	Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas
	Bonglack E.N.; Messinger J.E.; Cable J.M.; Chng J.; Mark Parnell K.; Reinoso-Vizcaíno N.M.; Barry A.P.; Russell V.S.; Dave S.S.; Christofk H.R.; Luftig M.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:25
英文摘要	Epstein–Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells—part of a phenomenon known as the “Warburg effect”— and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U-13C6–glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Epstein–Barr virus \| viral lymphoma \| lactate export \| monocarboxylate transporter \| cancer metabolism
语种	英语
scopus关键词	antineoplastic agent; azd 3965; electron transport chain complex I; Epstein Barr virus antigen 2; glutathione; lactic acid; LMP1 protein; monocarboxylate transporter; monocarboxylate transporter 1; monocarboxylate transporter 4; multienzyme complex; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide; unclassified drug; viral protein; Article; B lymphocyte; cell cycle arrest; cell proliferation; clinical effectiveness; controlled study; drug effect; drug efficacy; drug mechanism; drug response; Epstein Barr virus infection; human; human cell; lymphocyte proliferation; lymphoma; oxygen consumption rate; protein expression; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238515
作者单位	Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, United States; Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University School of Medicine, Durham, NC 27710, United States; IconOVir Bio. Inc., San Diego, CA 92121, United States; Department of Pediatrics, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Vettore, LLC, San Francisco, CA 94158, United States; Duke Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, United States; Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
推荐引用方式 GB/T 7714	Bonglack E.N.,Messinger J.E.,Cable J.M.,et al. Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas[J],2021,118(25).
APA	Bonglack E.N..,Messinger J.E..,Cable J.M..,Chng J..,Mark Parnell K..,...&Luftig M.A..(2021).Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.Proceedings of the National Academy of Sciences of the United States of America,118(25).
MLA	Bonglack E.N.,et al."Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas".Proceedings of the National Academy of Sciences of the United States of America 118.25(2021).