A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models

Xintaropoulou, Chrysi; Ward, Carol; Wise, Alan; Marston, Hugh; Turnbull, Arran; Langdon, Simon P.

doi:10.18632/oncotarget.4499

Cited by 130 publications

(99 citation statements)

References 58 publications

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“…After being internalized by tumor cells, PMLR nanosystem would be degraded by the endogenous H 2 O 2 in acidic lysosomes and then release 3PO to inhibit the glycolysis. This process was accompanied by the generation of O 2 , which could sensitize the inhibition effect of 3PO on glycolysis . Moreover, the camouflage of mRBC aimed to minimize the endocytosis of PMLR nanosystem by macrophages (one of the vital immune cells) through the “don't eat me” signal, thus alleviating the toxicity of PMLR nanosystem to the immune system.…”

Section: Methodsmentioning

confidence: 99%

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

et al. 2019

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Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)‐camouflaged hollow MnO2 (HMnO2) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long‐circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O2, which can be produced during the decomposition of endogenous H2O2 catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti‐PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.

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Section: Methodsmentioning

confidence: 99%

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

et al. 2019

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“…Phloretin is a well-known inhibitor of GLUTs and reduces the speed of glucose uptake into host cells (Xintaropoulou et al, 2015). Phloretin is a well-known inhibitor of GLUTs and reduces the speed of glucose uptake into host cells (Xintaropoulou et al, 2015).…”

Section: Glut Inhibitor Phloretin Enhances Hbv Replication By Upregmentioning

confidence: 99%

AMPK and Akt/mTOR signalling pathways participate in glucose‐mediated regulation of hepatitis B virus replication and cellular autophagy

Wang

Lin

Kemper

et al. 2019

Cellular Microbiology

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A growing consensus indicates that host metabolism plays a vital role in viral infections.Hepatitis B virus (HBV) infection occurs in hepatocytes with active glucose metabolism and may be regulated by cellular metabolism. We addressed the question whether and how glucose regulates HBV replication in hepatocytes. The low glucose concentration at 5 mM significantly promoted HBV replication via enhanced transcription and autophagy when compared with higher glucose concentrations (10 and 25 mM). At low glucose concentration, AMPK activity was increased and led to ULK1 phosphorylation at Ser 555 and LC3-II accumulation. By contrast, the mTOR pathway was activated by high glucose concentrations, resulting in reduced HBV replication. mTOR inhibition by rapamycin reversed negative effects of high glucose concentrations on HBV replication, suggesting that low glucose concentration promotes HBV replication by stimulating the AMPK/mTOR-ULK1-autophagy axis. Consistently, we found that glucose transporters inhibition using phloretin also enhanced HBV replication via increased AMPK/mTOR-ULK1-induced autophagy. Surprisingly, the glucose analogue 2-deoxy-D-glucose reduced HBV replication through activating the Akt/mTOR signalling pathway also at the low glucose concentrations. Our study reveals that glucose is an important factor for the HBV life cycle by regulating HBV transcription and posttranscriptional steps of HBV replication via cellular autophagy.

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“…The inhibition of Warburg effect deprives the generation of ATP, decreasing cancer cells growth and proliferation [10, 11]. Thus, Warburg effect has received substantial attention as a novel therapeutic target in cancers including lung cancer [12, 13], leukemia [14], breast cancer [15–18], pancreatic cancer [19, 20], colorectal cancer [21, 22], bladder cancer [23], and multiple myeloma [24, 25]. In multiple myeloma, dichloroacetate, which is an inhibitor of aerobic glycolysis, has been reported to increase myeloma cell sensitivity to bortezomib [24].…”

Section: Introductionmentioning

confidence: 99%

NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase

Xia

et al. 2017

J Hematol Oncol

101

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BackgroundAerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism of glucose and production of lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as a key player for regulating aerobic glycolysis and promoting tumor cell proliferation and survival.MethodsTandem affinity purification followed up by mass spectrometry (TAP-MS) and co-immunoprecipitation (Co-IP) were used to study the interaction between NIMA (never in mitosis gene A)-related kinase 2 (NEK2) and heterogeneous nuclear ribonucleoproteins (hnRNP) A1/2. RNA immunoprecipitation (RIP) was performed to identify NEK2 binding to PKM pre-mRNA sequence. Chromatin-immunoprecipitation (ChIP)-PCR was performed to analyze a transcriptional regulation of NEK2 by c-Myc. Western blot and real-time PCR were executed to analyze the regulation of PKM2 by NEK2.ResultsNEK2 regulates the alternative splicing of PKM immature RNA in multiple myeloma cells by interacting with hnRNPA1/2. RIP shows that NEK2 binds to the intronic sequence flanking exon 9 of PKM pre-mRNA. Knockdown of NEK2 decreases the ratio of PKM2/PKM1 and also other aerobic glycolysis genes including GLUT4, HK2, ENO1, LDHA, and MCT4. Myeloma patients with high expression of NEK2 and PKM2 have lower event-free survival and overall survival. Our data indicate that NEK2 is transcriptionally regulated by c-Myc in myeloma cells. Ectopic expression of NEK2 partially rescues growth inhibition and cell death induced by silenced c-Myc.ConclusionsOur studies demonstrate that NEK2 promotes aerobic glycolysis through regulating splicing of PKM and increasing the PKM2/PKM1 ratio in myeloma cells which contributes to its oncogenic activity.

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A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models

Cited by 130 publications

References 58 publications

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

AMPK and Akt/mTOR signalling pathways participate in glucose‐mediated regulation of hepatitis B virus replication and cellular autophagy

NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase

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