Selective down-regulation of human papillomavirus transcription by 2-deoxyglucose

Maehama, Toshiyuki; Patzelt, Andrea; Lengert, M; Hutter, K.‐J.; Kanazawa, Kazuki; Hausen, Harald zur; Rösl, Frank

doi:10.1002/(sici)1097-0215(19980529)76:5<639::aid-ijc5>3.0.co;2-r

Cited by 44 publications

(35 citation statements)

References 49 publications

(56 reference statements)

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“…Alternatively, aerobic glycolysis may be necessary to provide enzymes or cofactors necessary to maintain the latent state. Interestingly, 2DG was shown to inhibit human papillomavirus transcription and could play a role in the replication of KSHV during latency (29).…”

Section: Discussionmentioning

confidence: 99%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

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

201

233

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Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.human herpesvirus-8 | gamma-herpesvirus | latency | glycolysis

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Section: Discussionmentioning

confidence: 99%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

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

201

233

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“…Moreover, 2-DG mitigates disease progression in a murine model of temporal lobe epilepsy (8), possibly due to the repression of the BDNF promoter. 2-DG shows possibilities as an antiviral drug, as it targets gene expression in papillomavirus (9). Finally, 2-DG has been thoroughly studied in regard to cancer biology.…”

Section: -Deoxy-d-glucose (2-dg) Is a Stable Glucose Analogue Thatmentioning

confidence: 99%

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Ralser

Wamelink

Struys

et al. 2008

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

146

160

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The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.cell growth inhibition ͉ glycolysis ͉ off-target effect ͉ pentose phosphate pathway ͉ carbohydrate metabolism 2 -Deoxy-D-glucose (2-DG) is a stable glucose analogue that is actively taken up by the hexose transporters and phosphor ylated but cannot be fully metabolized. 2-DG-6-phosphate accumulates in the cell and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes. 2-DG-6-phosphate inhibits phosphoglucose isomerase (PGI) in a competitive, and hexokinase (HXK) in a noncompetitive, manner (1-3). On the cellular level, 2-DG provokes rapid growth inhibition and results in altered glycosylation that is highly dependent on catabolic glucose intermediates (4, 5).2-DG has been used in numerous studies focused on the effects of reduced metabolic rates. Recently, 2-DG has been used in this study of glycolytic inhibition with respect to calorie restriction and aging. 2-DG increases the lifespan of C. elegans, an effect that is reversed by antioxidants (6, 7). Moreover, 2-DG mitigates disease progression in a murine model of temporal lobe epilepsy (8), possibly due to the repression of the BDNF promoter. 2-DG shows possibilities as an antiviral drug, as it targets gene expression in papillomavirus (9). Finally, 2-DG has been thoroughly studied in regard to cancer biology. Malignant cells exhibit increased glucose metabolism compared with surrounding tissue (10) and, therefore, increased 2-DG uptake. 2-DG efficiently inhibits tumor progression and is a focus of clinical trials (reviewed in ref. 11).In general, it is assumed that the biological effects of 2-DG are the consequence of a block in carbohydrate catalysis, implying that 2-DG treated cells, unable to metabolize glucose, stop growing as a result of a lack of energy and metabolic intermediates. However, several observations bring this assumption into question. First, only a moderate decline in ATP has been observed in 2-DG-treated eukaryotes (7,12). Second, a current study reveals that tumor cells react differently to 2-DG than to its close analogue 2-fluorod...

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“…In a previous study (33), human papillomavirus (HPV) early gene transcription was shown to be suppressed in HeLa cervical carcinoma cells and its derivative cells by the treatment of 2-DG, and it was postulated that high glucose availability is indispensable for both high glycolysis rate of cervical cancer cells and the maintenance of the carcinogenic state by continued expression of HPV oncoproteins. However, the molecular mechanism by which 2-DG treatment caused down-regulation of HPV gene expression was not investigated.…”

mentioning

confidence: 99%

Down-regulation of Sp1 Activity through Modulation of O-Glycosylation by Treatment with a Low Glucose Mimetic, 2-Deoxyglucose

Kang

Cho

et al. 2003

Journal of Biological Chemistry

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2-Deoxyglucose (2-DG), a nonmetabolizable glucose analogue, blocks glycolysis at the phosphohexose isomerase step and has been frequently used as a glucose starvation mimetic in studies of a wide variety of physiological dysfuctions. However, the effect of 2-DG on protein glycosylation and related signal pathways has not been investigated in depth. In HeLa, an HPV18-positive cervical carcinoma line, 2-DG treatment downregulates human papillomavirus early gene transcription. This down-regulation was also achieved by low glucose supply or hypoxia, suggesting that this is a response commonly modulated by cellular glucose or energy level. We investigated how 2-DG and low glucose affect transcriptional activity. Human papillomavirus gene transcription was only marginally affected by the inhibition of ATP synthesis or the supplementation of pyruvate to 2-DG-treated cells, suggesting that poor ATP generation is involved only to a limited extent. 2-DG treatment also inhibited activation of p21 WAF1 promoter, which is controlled by p53 and/or Sp1. In a reporter assay using p21 WAF1 promoter constructs, 2-DG exerted a strong inhibitory effect on Sp1 activity. DNA binding activity of Sp1 in 2-DG-treated HeLa cells was intact, whereas it was severely impaired in cells incubated in a low glucose medium or in hypoxic condition. Unexpectedly, Sp1 was heavily modified with GlcNAc in 2-DG-treated cells, which is at least partially attributed to the inhibitory effect of 2-DG on N-acetyl-␤-D-glucosaminidase activity. Our results suggest that 2-DG, like low glucose or hypoxic condition, down-regulates Sp1 activity, but through hyper-GlcNAcylation instead of hypo-GlcNAcylation.

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Selective down-regulation of human papillomavirus transcription by 2-deoxyglucose

Cited by 44 publications

References 49 publications

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Down-regulation of Sp1 Activity through Modulation of O-Glycosylation by Treatment with a Low Glucose Mimetic, 2-Deoxyglucose

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