Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme

2011 ◽  
Vol 44 (1) ◽  
pp. 84-91 ◽  
Author(s):  
Amparo Wolf ◽  
Sameer Agnihotri ◽  
Diana Munoz ◽  
Abhijit Guha
Keyword(s):  
Glioblastoma Multiforme ◽  
Glycolytic Enzyme ◽  
Normal Brain ◽  
Developmental Profile ◽  
Hexokinase 2

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

2011 ◽  
Vol 208 (2) ◽  
pp. 313-326 ◽  
Author(s):  
Amparo Wolf ◽  
Sameer Agnihotri ◽  
Johann Micallef ◽  
Joydeep Mukherjee ◽  
Nesrin Sabha ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Glycolytic Enzyme ◽  
Low Grade ◽  
Normal Brain ◽  
Hexokinase 2 ◽  
Human Glioblastoma ◽  
Human Glioblastoma Multiforme ◽  
The Warburg Effect

Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the “Warburg effect.” Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1α and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs.

Abstract 40: Developmental profile and regulation of the glycolytic enzyme hexokinase 2 and its association with aerobic glycolysis

2010 ◽  
Author(s):  
Amparo M. Wolf ◽  
Sameer Agnihotri ◽  
Diana M. Munoz-Gajadhar ◽  
Cynthia Hawkins ◽  
Abhijit Guha
Keyword(s):  
Aerobic Glycolysis ◽  
Glycolytic Enzyme ◽  
Developmental Profile ◽  
Hexokinase 2

Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines

2016 ◽  
Vol 94 (3) ◽  
pp. 247-255 ◽  
Author(s):  
Ruiting Li ◽  
Yinghui Li ◽  
Xin Hu ◽  
Haiwei Lian ◽  
Lei Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glioblastoma Multiforme ◽  
Cell Lines ◽  
Normal Brain ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Factor ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration ◽  
Transcription Factor 3

Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase–Akt and MAPK–Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways.

scholarly journals ANGI-06. FUNCTION OF FORMIN-LIKE 1 (FMNL1) IN GLIOBLASTOMA MULTIFORME

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Nayuta Higa ◽  
Yoshinari Shinsato ◽  
Tomoko Takajyo ◽  
Hajime Yonezawa ◽  
Hiroyuki Uchida ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Cancer Progression ◽  
Morphological Changes ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
University Hospital ◽  
Migration And Invasion ◽  
Normal Brain ◽  
Filamentous Actin ◽  
Invasion And Migration

Abstract INTRODUCTION Glioblastoma multiforme is the most common primary malignant brain tumour in adults. It is characterised by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in cancer progression, invasion, and migration. However, the role of FMNL1 in cancer remains unclear. We are the first to investigate FMNL1 in GBM. METHODS Clinical specimens were obtained from tumours surgically removed and pathologically confirmed as GBM from 217 GBM patients treated from 2000 to 2015 at the Department of Neurosurgery, Kagoshima University Hospital. We studied the expression of FMNL1 in glioblastoma samples by immunohistochemistry to analyse the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from TCGA and analysed using Gene Set Enrichment Analysis (GSEA). RESULTS FMNL1 was found to be a predictor of poor prognosis in a cohort of 217 cases (P < 0.001). GSEA showed that upregulation and downregulation of FMNL1 were associated with mesenchymal and proneural markers, respectively. Contrarily, downregulation of FMNL1 suppressed migration and invasion of glioblastoma multiforme cells via DIAPH1 and GOLGA2, respectively. Downregulation of FMNL1 also suppressed assembly of actin fibres, induced morphological changes, and diminished filamentous actin. CONCLUSION Our studies show that abundant FMNL1 expression in GBM patients is correlated with an unfavourable prognosis. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.

scholarly journals Low GAS5 Levels as a Predictor of Poor Survival in Patients with Lower-Grade Gliomas

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yanfang Wang ◽  
Shan Xin ◽  
Kai Zhang ◽  
Run Shi ◽  
Xuanwen Bao
Keyword(s):  
Overall Survival ◽  
Glioblastoma Multiforme ◽  
Translation Initiation ◽  
Noncoding Rna ◽  
Rank Test ◽  
Molecular Characteristics ◽  
Normal Brain ◽  
Lower Grade ◽  
Ribosomal Biogenesis ◽  
Rna Seq

Introduction. Gliomas are infiltrative neoplasms of a highly invasive nature. Different stages of gliomas feature distinct genomic, genetic, and epigenetic changes. The long noncoding RNA Growth Arrest Specific Transcript 5 (GAS5) is an identified tumour suppressor involved in several cancers. However, the underlying roles of the GAS5 gene in lower-grade glioma (LGG) patients are not clear. Methods. Via bioinformatic analysis based on TCGA-LGG and TCGA-GBM data, we explored the mechanisms of GAS5 expression in LGG (grades II and III) and high-grade glioma (glioblastoma multiforme, grade IV). The log-rank test and multivariate Cox analysis were performed to find the association between GAS5 and overall survival (OS) in LGG patients. Weighted gene coexpression network analysis (WGCNA) and RNA-Seq analysis were applied to find the key gene network associated with GAS5. Results. We found that GAS5 expression was downregulated in both LGG and glioblastoma multiforme (GBM) compared with normal brain tissue. Low methylation in the GAS5 promoter region was detected in both LGG and GBM tissues. The amplification type was the predominant type of GAS5 gene alteration in both LGG and GBM. High GAS5 expression was more associated with long overall survival (OS) in LGG patients than in GBM patients. The multivariate survival analysis of GAS5 and clinical and molecular characteristics in LGG patients further confirmed the association between GAS5 and OS in LGG patients. We then developed a nomogram for clinical use. WGCNA and RNA-Seq analysis indicated that ribosomal biogenesis and translation initiation were the predominant events regulated by GAS5 in LGG patients. Conclusion. Taken together, these results demonstrate that GAS5 expression is associated with OS in LGG patients and that its underlying roles involve the regulation of ribosomal biogenesis and translation initiation, which may aid in identifying a new target for the treatment of LGG.

scholarly journals PP06. HYPOMETHYLATION OF HEXOKINASE 2 IS A FREQUENT EVENT IN GLIOBLASTOMA MULTIFORME

2017 ◽  
Vol 19 (suppl_1) ◽  
pp. i2-i2
Author(s):  
Mr Daniel Blakeway ◽  
Dr Katherine Karakoula ◽  
Dr Mark Morris ◽  
Mr Lawrence Eagles ◽  
Dr Farjana Begam Rowther ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Hexokinase 2 ◽  
Frequent Event

scholarly journals Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

2019 ◽  
Author(s):  
Mitsugu Shimobayashi ◽  
Sunil Shetty ◽  
Irina C. Frei ◽  
Bettina K. Wölnerhanssen ◽  
Diana Weissenberger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Blood Glucose ◽  
Underlying Mechanism ◽  
Glycolytic Enzyme ◽  
Diabetic Patients ◽  
Loss Of Function ◽  
Hexokinase 2 ◽  
High Blood Glucose ◽  
Glucose Levels ◽  
Blood Glucose Levels

AbstractChronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here we show that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia.One Sentence SummaryLoss of the glycolytic enzyme Hexokinase 2 in adipose tissue is a mechanism underlying high blood glucose levels.

scholarly journals Lipid accumulation and oxidation in glioblastoma multiforme

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bouchra Taïb ◽  
Amine M. Aboussalah ◽  
Mohammed Moniruzzaman ◽  
Suming Chen ◽  
Norman J. Haughey ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Glioblastoma Multiforme ◽  
Lipid Droplets ◽  
Monounsaturated Fatty Acids ◽  
Acid Oxidation ◽  
Normal Brain ◽  
Lipid Species ◽  
Brain Tissues

AbstractGlioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite the multimodal standard treatments for GBM, the median survival is still about one year. Analysis of brain tissues from GBM patients shows that lipid droplets are highly enriched in tumor tissues while undetectable in normal brain tissues, yet the identity and functions of lipid species in GBM are not well understood. The aims of the present work are to determine how GBM utilizes fatty acids, and assess their roles in GBM proliferation. Treatment of U138 GBM cells with a monounsaturated fatty acid, oleic acid, induces accumulation of perilipin 2-coated lipid droplets containing triglycerides enriched in C18:1 fatty acid, and increases fatty acid oxidation. Interestingly, oleic acid also increases glucose utilization and proliferation of GBM cells. In contrast, pharmacologic inhibition of monoacylglycerol lipase attenuates GBM proliferation. Our findings demonstrate that monounsaturated fatty acids promote GBM proliferation via triglyceride metabolism, suggesting a novel lipid droplet-mediated pathway which may be targeted for GBM treatment.

scholarly journals Glycolipid GD3 and GD3 synthase are key drivers for glioblastoma stem cells and tumorigenicity

2016 ◽  
Vol 113 (20) ◽  
pp. 5592-5597 ◽  
Author(s):  
Shih-Chi Yeh ◽  
Pao-Yuan Wang ◽  
Yi-Wei Lou ◽  
Kay-Hooi Khoo ◽  
Michael Hsiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Glioblastoma Multiforme ◽  
Normal Brain ◽  
Self Renewal ◽  
Complement Dependent Cytotoxicity ◽  
Gd3 Synthase ◽  
Key Drivers ◽  
Human Gbm

The cancer stem cells (CSCs) of glioblastoma multiforme (GBM), a grade IV astrocytoma, have been enriched by the expressed marker CD133. However, recent studies have shown that CD133− cells also possess tumor-initiating potential. By analysis of gangliosides on various cells, we show that ganglioside D3 (GD3) is overexpressed on eight neurospheres and tumor cells; in combination with CD133, the sorted cells exhibit a higher expression of stemness genes and self-renewal potential; and as few as six cells will form neurospheres and 20–30 cells will grow tumor in mice. Furthermore, GD3 synthase (GD3S) is increased in neurospheres and human GBM tissues, but not in normal brain tissues, and suppression of GD3S results in decreased GBM stem cell (GSC)-associated properties. In addition, a GD3 antibody is shown to induce complement-dependent cytotoxicity against cells expressing GD3 and inhibition of GBM tumor growth in vivo. Our results demonstrate that GD3 and GD3S are highly expressed in GSCs, play a key role in glioblastoma tumorigenicity, and are potential therapeutic targets against GBM.

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