Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme

Wolf, Amparo; Agnihotri, Sameer; Micallef, Johann; Mukherjee, Joydeep; Sabha, Nesrin; Cairns, Rob A.; Hawkins, Cynthia; Guha, Abhijit

doi:10.1084/jem.20101470

Cited by 656 publications

(582 citation statements)

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“…One hundred nanograms of cDNA was used in SsoAdvanced SYBR green Supermix (Bio-Rad) according to the manufacturer's protocols. The primers used for hexokinase 2 (HK2) (22), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (23), DENV RNA (24), and hypoxanthine-guanine phosphoribosyltransferase (HPRT) (10) have been described previously. Relative abundances of HK2 mRNA or DENV RNA were normalized by the delta threshold cycle method to the abundance of GAPDH or HPRT mRNA, with mock-infected cells set to 1 or DENVinfected cells fed replete medium set to 100.…”

Section: Cells and Virusesmentioning

confidence: 99%

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Dengue Virus Induces and Requires Glycolysis for Optimal Replication

Fontaine

Sanchez

Camarda

et al. 2015

J Virol

259

272

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Viruses rely on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. Dengue virus (DENV), a member of the Flaviviridae family, is one of the most important arthropod-borne human pathogens worldwide. We analyzed global intracellular metabolic changes associated with DENV infection of primary human cells. Our metabolic profiling data suggested that central carbon metabolism, particularly glycolysis, is strikingly altered during a time course of DENV infection. Glucose consumption is increased during DENV infection and depriving DENV-infected cells of exogenous glucose had a pronounced impact on viral replication. Furthermore, the expression of both glucose transporter 1 and hexokinase 2, the first enzyme of glycolysis, is upregulated in DENV-infected cells. Pharmacologically inhibiting the glycolytic pathway dramatically reduced DENV RNA synthesis and infectious virion production, revealing a requirement for glycolysis during DENV infection. Thus, these experiments suggest that DENV induces the glycolytic pathway to support efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat DENV infection in the future. IMPORTANCEApproximately 400 million people are infected with dengue virus (DENV) annually, and more than one-third of the global population is at risk of infection. As there are currently no effective vaccines or specific antiviral therapies for DENV, we investigated the impact DENV has on the host cellular metabolome to identify metabolic pathways that are critical for the virus life cycle. We report an essential role for glycolysis during DENV infection. DENV activates the glycolytic pathway, and inhibition of glycolysis significantly blocks infectious DENV production. This study provides further evidence that viral metabolomic analyses can lead to the discovery of novel therapeutic targets to block the replication of medically important human pathogens. Viruses are obligate intracellular parasites that depend on the metabolic machinery of the host cell to supply the energy and macromolecules necessary for successful replication. In recent years, research has focused on investigating how virus infection alters host metabolism with the hope that these studies will provide insight into the metabolic requirements of viral replication. Viral modulation of the host cell metabolic profile has been examined for several viruses, including human cytomegalovirus (HCMV), herpes simplex virus 1 (HSV-1), hepatitis C virus, influenza A virus, human immunodeficiency virus type 1 (HIV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), and Epstein-Barr virus (1-11). These reports revealed that virus infection triggers dramatic changes in cellular metabolism, particularly in central carbon utilization pathways.Glucose and glutamine represent the two main carbon sources used to support the energetic and biosynthetic needs of mammalian cells. In...

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Section: Cells and Virusesmentioning

confidence: 99%

“…Hexokinase is the first rate-limiting enzyme of the glycolytic pathway and the HK2 isoform, in particular, has been shown to be a key mediator of aerobic glycolysis (22,28). We utilized real-time RT-qPCR to measure HK2 mRNA levels during DENV infection.…”

Section: Denv Infection Alters Glucose Metabolismmentioning

confidence: 99%

Dengue Virus Induces and Requires Glycolysis for Optimal Replication

Fontaine

Sanchez

Camarda

et al. 2015

J Virol

259

272

View full text Add to dashboard Cite

show abstract

“…Було встановлено, що пептиди, які утворюються з біфункціонального сигнального ензиму ERN1 в процесі протеолізу цього протеїну мають здатність модулювати активність біфункціонального ензиму ERN1і захищати клітини від стресу ендоплазматич-ного ретикулума [33]. о. г. мІНчеНКо, А. П. хАРьКоВА, Т. В. БАКАлеЦь, І. В. КРиВДюК роль стресу ендоплазматичного ретикулума та гіпоксії в рості злоякісних пухлин гіпоксія є характерною рисою більшості злоякісних пухлин і тісно пов'язана не лише з ростом пухлин, а і з метастазуванням та резистентністю до лікування [19,[34][35][36]. гіпоксія є одним із обов'язкових факторів злоякісного росту, оскільки виражено активує процеси проліферації, зокрема за рахунок активації гліколізу і пентозо-фосфатного циклу, через що пухлинні клітини харак-теризуються посиленим гліколізом та висо-ким рівнем лактату і пірувату, що корелює зі збільшеним рівнем експресії ензимів гліколізу та переносників глюкози завдяки механізмам опосередкованих транскрипційним факто-ром HIF (фактор, що індукується за гіпоксії) [37][38][39][40].…”

Section: рис 3 схематичне зображення структури Ern1 в ендоплазматичunclassified

Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia

Minchenko¹,

Kharkova²,

Bakalets³

et al. 2013

Ukr.Biochem.J.

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“…Like LDHB, HKII is also reported to be crucial for the Warburg effect and tumor progression. 11 Therefore components in these mTORC1-glycolytic enzymes pathways could be targeted for the treatment of disorders caused by the abnormal mTORC1 signaling.…”

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confidence: 99%