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Article: Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas.

Udutha, Suresh / Taglang, Céline / Batsios, Georgios / Gillespie, Anne Marie / Tran, Meryssa / Ronen, Sabrina M / Ten Hoeve, Johanna / Graeber, Thomas G / Viswanath, Pavithra

bioRxiv : the preprint server for biology

2023

Abstract: Telomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in ... ...

Abstract	Telomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of Significance: Using
Language	English
Publishing date	2023-11-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.14.566937
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Article: Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.

Muranaka, Hayato / Billet, Sandrine / Cruz-Hernández, Carlos / Ten Hoeve, Johanna / Gonzales, Gabrielle / Elmadbouh, Omer / Zhang, Le / Smith, Bethany / Tighiouart, Mourad / You, Sungyong / Edderkaoui, Mouad / Hendifar, Andrew / Pandol, Stephen / Gong, Jun / Bhowmick, Neil

Research square

2023

Abstract: Limited efficacy of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) patients contributes to high mortality. Cancer cells develop strategies to secure nutrients in nutrient-deprived conditions and chemotherapy treatment. Despite the ... ...

Abstract	Limited efficacy of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) patients contributes to high mortality. Cancer cells develop strategies to secure nutrients in nutrient-deprived conditions and chemotherapy treatment. Despite the dependency of PDAC on glutamine (Gln) for growth and survival, strategies designed to suppress Gln metabolism have limited effects. Here, we demonstrated that supraphysiological concentrations of glutamine (SPG) could produce paradoxical responses leading to tumor growth inhibition alone and in combination with chemotherapy. Integrated metabolic and transcriptomic analysis revealed that the growth inhibitory effect of SPG was the result of a decrease in intracellular amino acid and nucleotide pools. Mechanistically, disruption of the sodium gradient, plasma membrane depolarization, and competitive inhibition of amino acid transport mediated amino acid deprivation. Among standard chemotherapies given to PDAC patients, gemcitabine treatment resulted in a significant enrichment of amino acid and nucleoside pools, exposing a metabolic vulnerability to SPG-induced metabolic alterations. Further analysis highlighted a superior anticancer effect of D-glutamine, a non-metabolizable enantiomer of the L-glutamine, by suppressing both amino acid uptake and glutaminolysis, in gemcitabine-treated preclinical models with no apparent toxicity. Our study suggests supraphysiological glutamine could be a means of inhibiting amino acid uptake and nucleotide biosynthesis, potentiating gemcitabine sensitivity in PDAC.
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3647514/v1
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Article ; Online: A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.

Palermo, Amelia / Li, Shen / Ten Hoeve, Johanna / Chellappa, Akshay / Morris, Alexandra / Dillon, Barbara / Ma, Feiyang / Wang, Yijie / Cao, Edward / Shabane, Byourak / Acín-Perez, Rebeca / Petcherski, Anton / Lusis, A Jake / Hazen, Stanley / Shirihai, Orian S / Pellegrini, Matteo / Arumugaswami, Vaithilingaraja / Graeber, Thomas G / Deb, Arjun

Communications biology

2023 Volume 6, Issue 1, Page(s) 1115

Abstract: The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity ... ...

Abstract	The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.
MeSH term(s)	Mice ; Animals ; SARS-CoV-2 ; Diet, Ketogenic ; COVID-19 ; Inflammation ; Cytokines
Chemical Substances	Cytokines
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05478-7
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Article ; Online: Ciliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas.

Do Rhee, Kun / Wang, Yanjie / Ten Hoeve, Johanna / Stiles, Linsey / Nguyen, Thao Thi Thu / Zhang, Xiangmei / Vergnes, Laurent / Reue, Karen / Shirihai, Orian / Bok, Dean / Yang, Xian-Jie

Nature communications

2022 Volume 13, Issue 1, Page(s) 7037

Abstract: Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a ... ...

Abstract	Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a mouse model of photoreceptor degeneration. CNTF treatment improves the morphology of photoreceptor mitochondria, but also leads to reduced oxygen consumption and suppressed respiratory chain activities. Molecular analyses show elevated glycolytic pathway gene transcripts and active enzymes. Metabolomics analyses detect significantly higher levels of ATP and the energy currency phosphocreatine, elevated glycolytic pathway metabolites, increased TCA cycle metabolites, lipid biosynthetic pathway intermediates, nucleotides, and amino acids. Moreover, CNTF treatment restores the key antioxidant glutathione to the wild type level. Therefore, CNTF significantly impacts the metabolic status of degenerating retinas by promoting aerobic glycolysis and augmenting anabolic activities. These findings reveal cellular mechanisms underlying enhanced neuronal viability and suggest potential therapies for treating retinal degeneration.
MeSH term(s)	Mice ; Animals ; Ciliary Neurotrophic Factor/genetics ; Ciliary Neurotrophic Factor/metabolism ; Retinal Degeneration/therapy ; Neuroprotection ; Retina/metabolism ; Glycolysis
Chemical Substances	Ciliary Neurotrophic Factor
Language	English
Publishing date	2022-11-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34443-x
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Article ; Online: Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.

Bennett, Neal K / Nakaoka, Hiroki J / Laurent, Danny / Okimoto, Ross A / Sei, Yoshitaka / Horvai, Andrew E / Bivona, Trever G / Ten Hoeve, Johanna / Graeber, Thomas G / Nakamura, Ken / Nakamura, Jean L

PLoS biology

2022 Volume 20, Issue 9, Page(s) e3001753

Abstract: The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and ... ...

Abstract	The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.
MeSH term(s)	Cell Line, Tumor ; Glycolysis/genetics ; Humans ; Lung Neoplasms/pathology ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Ribosomal Proteins/metabolism
Chemical Substances	Mitochondrial Proteins ; Ribosomal Proteins
Language	English
Publishing date	2022-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3001753
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Article ; Online: Mitohormesis reprogrammes macrophage metabolism to enforce tolerance.

Timblin, Greg A / Tharp, Kevin M / Ford, Breanna / Winchester, Janet M / Wang, Jerome / Zhu, Stella / Khan, Rida I / Louie, Shannon K / Iavarone, Anthony T / Ten Hoeve, Johanna / Nomura, Daniel K / Stahl, Andreas / Saijo, Kaoru

Nature metabolism

2021 Volume 3, Issue 5, Page(s) 618–635

Abstract: Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts ...

Abstract	Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically driven and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state wherein stimulus-induced pro-inflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyoestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species are TLR-dependent signalling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signalling and pharmacologically triggering mitohormesis represents a new anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of pro-inflammatory gene transcription by mitochondria.
MeSH term(s)	Acetyl Coenzyme A/metabolism ; Anti-Inflammatory Agents/pharmacology ; Cellular Reprogramming ; Energy Metabolism ; Estrogens/metabolism ; Gene Expression Regulation ; Immune Tolerance ; Lipopolysaccharides/immunology ; Macrophage Activation ; Macrophages/immunology ; Macrophages/metabolism ; Mitochondria/metabolism ; Models, Biological ; Reactive Oxygen Species/metabolism ; Stress, Physiological
Chemical Substances	Anti-Inflammatory Agents ; Estrogens ; Lipopolysaccharides ; Reactive Oxygen Species ; Acetyl Coenzyme A (72-89-9)
Language	English
Publishing date	2021-05-20
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-021-00392-w
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Article ; Online: M2 isoform of pyruvate kinase rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance.

Bailleul, Justine / Ruan, Yangjingyi / Abdulrahman, Lobna / Scott, Andrew J / Yazal, Taha / Sung, David / Park, Keunseok / Hoang, Hanna / Nathaniel, Juan / Chu, Fang-I / Palomera, Daisy / Sehgal, Anahita / Tsang, Jonathan E / Nathanson, David A / Xu, Shili / Park, Junyoung O / Ten Hoeve, Johanna / Bhat, Kruttika / Qi, Nathan /

Kornblum, Harley I / Schaue, Dorthe / McBride, William H / Lyssiotis, Costas A / Wahl, Daniel R / Vlashi, Erina

Neuro-oncology

2023 Volume 25, Issue 11, Page(s) 1989–2000

Abstract: Background: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we ...

Abstract	Background: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance. Methods: Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with M2 isoform of pyruvate kinase (PKM2) activity was tested via gliomasphere formation assays and in vivo human GBM models. Results: Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the PKM2. Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo. Conclusions: These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.
MeSH term(s)	Humans ; Pyruvate Kinase/metabolism ; Glioblastoma/metabolism ; Antioxidants ; Protein Isoforms ; Glucose/metabolism ; Cell Line, Tumor
Chemical Substances	Pyruvate Kinase (EC 2.7.1.40) ; Antioxidants ; Protein Isoforms ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-06-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noad103
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Article ; Online: Defining the ATPome reveals cross-optimization of metabolic pathways.

Bennett, Neal K / Nguyen, Mai K / Darch, Maxwell A / Nakaoka, Hiroki J / Cousineau, Derek / Ten Hoeve, Johanna / Graeber, Thomas G / Schuelke, Markus / Maltepe, Emin / Kampmann, Martin / Mendelsohn, Bryce A / Nakamura, Jean L / Nakamura, Ken

Nature communications

2020 Volume 11, Issue 1, Page(s) 4319

Abstract: Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP-the ATPome-we conducted a genome-wide ... ...

Abstract	Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP-the ATPome-we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.
MeSH term(s)	Adenosine Triphosphate/genetics ; Adenosine Triphosphate/metabolism ; CRISPR-Cas Systems ; Cell Line ; Energy Metabolism ; Female ; Fibroblasts ; Gene Expression Regulation ; Gene Knockdown Techniques ; Glucose/metabolism ; Glycolysis/physiology ; Hexokinase/genetics ; Hexokinase/metabolism ; Humans ; K562 Cells ; Metabolic Networks and Pathways/genetics ; Metabolic Networks and Pathways/physiology ; Metabolomics ; Mitochondria/metabolism ; Pentose Phosphate Pathway ; Point Mutation
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; Hexokinase (EC 2.7.1.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-08-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18084-6
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Article ; Online: Ampk regulates IgD expression but not energy stress with B cell activation.

Waters, Lynnea R / Ahsan, Fasih M / Ten Hoeve, Johanna / Hong, Jason S / Kim, Diane N H / Minasyan, Aspram / Braas, Daniel / Graeber, Thomas G / Zangle, Thomas A / Teitell, Michael A

Scientific reports

2019 Volume 9, Issue 1, Page(s) 8176

Abstract: Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major ... ...

Abstract	Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major upstream kinase for Ampk, had critical and unexpected roles in activating naïve B cells and in germinal center formation. Therefore, we examined whether Lkb1 activities during B cell activation depend on Ampk and report surprising Ampk activation with in vitro B cell stimulation in the absence of energy stress, coupled to rapid biomass accumulation. Despite Ampk activation and a controlling role for Lkb1 in B cell activation, Ampk knockout did not significantly affect B cell activation, differentiation, nutrient dynamics, gene expression, or humoral immune responses. Instead, Ampk loss specifically repressed the transcriptional expression of IgD and its regulator, Zfp318. Results also reveal that early activation of Ampk by phenformin treatment impairs germinal center formation but does not significantly alter antibody responses. Combined, the data show an unexpectedly specific role for Ampk in the regulation of IgD expression during B cell activation.
MeSH term(s)	AMP-Activated Protein Kinase Kinases ; AMP-Activated Protein Kinases ; Adenosine Triphosphate/metabolism ; Anabolic Agents/pharmacology ; Animals ; B-Lymphocytes/drug effects ; B-Lymphocytes/metabolism ; Cyclic AMP Receptor Protein/drug effects ; Cyclic AMP Receptor Protein/genetics ; DNA-Binding Proteins/genetics ; Energy Metabolism/drug effects ; Energy Metabolism/genetics ; Gene Expression Regulation/drug effects ; Germinal Center/drug effects ; HeLa Cells ; Humans ; Immunoglobulin D/genetics ; Metabolomics ; Phenformin/pharmacology ; Protein Kinases/genetics ; Protein Serine-Threonine Kinases/genetics
Chemical Substances	Anabolic Agents ; Cyclic AMP Receptor Protein ; DNA-Binding Proteins ; Immunoglobulin D ; Zfp318 protein, mouse ; Adenosine Triphosphate (8L70Q75FXE) ; Phenformin (DD5K7529CE) ; Protein Kinases (EC 2.7.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Stk11 protein, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinase Kinases (EC 2.7.11.3) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2019-06-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-43985-y
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Article: R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

Qing, Ying / Dong, Lei / Gao, Lei / Li, Chenying / Li, Yangchan / Han, Li / Prince, Emily / Tan, Brandon / Deng, Xiaolan / Wetzel, Collin / Shen, Chao / Gao, Min / Chen, Zhenhua / Li, Wei / Zhang, Bin / Braas, Daniel / ten Hoeve, Johanna / Sanchez, Gerardo Javier / Chen, Huiying /

Chan, Lai N / Chen, Chun-Wei / Ann, David / Jiang, Lei / Müschen, Markus / Marcucci, Guido / Plas, David R / Li, Zejuan / Su, Rui / Chen, Jianjun

Molecular cell. 2021 Mar. 04, v. 81, no. 5

2021

Abstract: R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively ... ...

Abstract	R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N⁶-methyladenosine (m⁶A)/YTH N⁶-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34⁺ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism.
Keywords	RNA ; RNA-binding proteins ; antineoplastic activity ; genes ; glycolysis ; humans ; lactate dehydrogenase ; metabolites ; mutants ; myeloid leukemia ; neoplasm cells ; phosphofructokinases ; stem cells ; therapeutics
Language	English
Dates of publication	2021-0304
Size	p. 922-939.e9.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.12.026
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