The Warburg effect: molecular aspects and therapeutic possibilities

Ngo, Hanh Giai; Tortorella, Stephanie M.; Ververis, Katherine; Karagiannis, Tom C.

doi:10.1007/s11033-014-3764-7

Cited by 76 publications

(51 citation statements)

References 78 publications

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“…Additionally, aerobic glycolysis was found to affect the cells signaling of tumor cells through maintaining the appropriate balance of reactive oxygen species (ROS) and histone acetylation [1, 6, 8]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

Xia

et al. 2017

J Hematol Oncol

100

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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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Section: Introductionmentioning

confidence: 99%

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

Xia

et al. 2017

J Hematol Oncol

100

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“…The dysregulation of cellular respiration, which is common in cancer cells, is better known as the Warburg effect or aerobic glycolysis, whereby cells metabolize glucose via glycolysis in preference to oxidative phosphorylation as the primary means of energy generation [1,2]. Glutamine is another key nutrient that plays a pivotal role in metabolic processes within proliferating tumour cells, including production of energy for biological processes, protection against oxidative stress and providing both carbon and nitrogen sources for macromolecule synthesis [3,4,5].…”

Section: Introductionmentioning

confidence: 99%

Optimized Method for Untargeted Metabolomics Analysis of MDA-MB-231 Breast Cancer Cells

et al. 2016

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Cancer cells often have dysregulated metabolism, which is largely characterized by the Warburg effect—an increase in glycolytic activity at the expense of oxidative phosphorylation—and increased glutamine utilization. Modern metabolomics tools offer an efficient means to investigate metabolism in cancer cells. Currently, a number of protocols have been described for harvesting adherent cells for metabolomics analysis, but the techniques vary greatly and they lack specificity to particular cancer cell lines with diverse metabolic and structural features. Here we present an optimized method for untargeted metabolomics characterization of MDA-MB-231 triple negative breast cancer cells, which are commonly used to study metastatic breast cancer. We found that an approach that extracted all metabolites in a single step within the culture dish optimally detected both polar and non-polar metabolite classes with higher relative abundance than methods that involved removal of cells from the dish. We show that this method is highly suited to diverse applications, including the characterization of central metabolic flux by stable isotope labelling and differential analysis of cells subjected to specific pharmacological interventions.

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“…The Warburg effect states that cancer cells can secrete lactic acid (5). ECs are surrounded by a high lactic acid environment, which can activate numerous signaling pathways and promote EC proliferation (6,7).…”

Section: Introductionmentioning

confidence: 99%

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Wang

Liu

et al. 2016

Oncology Reports

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Abstract. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) and monocarboxylate transporter 1 (MCT1) play important roles in tumor endothelial cells (ECs) and several biological processes. The present study was conducted to study the effects of PFKFB3 and MCT1 on cell proliferation and apoptosis in the tumor microenvironment by co-culture of HUVECs and T24, a bladder cancer (BC) cell line, using a microfluidic device. Immunofluorescence assay showed that HUVEC activity was significantly enhanced under co-culture with T24 cells, according to the stronger fluorescence intensity of CD31 and CD105 than that in the signal-cultured cells. Quercetin treatment inhibited MCT1 expression but did not affect PFKFB3 expression. Knockdown of MCT1 or/and PFKFB3 increased the apoptosis rate of the HUVECs under single-culture and co-culture situations by staining with calcein and propidium iodide. Meanwhile, cell proliferation and lactic concentration were significantly decreased after the blocking of MCT1 or/and PFKFB3, as compared with that in the control group. No obvious differences in the effects on apoptosis, proliferation and lactic concentration were found between cells treated with quercetin and siMCT1. Thus, we concluded that the targeting of MCT1 and PFKFB3 regulated cell proliferation and apoptosis in BC cells by altering the tumor microenvironment, and quercetin exhibited a potential antitumor effect by targeting MCT1.

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The Warburg effect: molecular aspects and therapeutic possibilities

Cited by 76 publications

References 78 publications

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

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

Optimized Method for Untargeted Metabolomics Analysis of MDA-MB-231 Breast Cancer Cells

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

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