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 ◽  
...  

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.

2011 ◽  
Vol 192 (2) ◽  
pp. i1-i1 ◽  
Author(s):  
Amparo Wolf ◽  
Sameer Agnihotri ◽  
Johann Micallef ◽  
Joydeep Mukherjee ◽  
Nesrin Sabha ◽  
...  

2019 ◽  
Author(s):  
Maria V. Liberti ◽  
Annamarie E. Allen ◽  
Vijyendra Ramesh ◽  
Ziwei Dai ◽  
Katherine R. Singleton ◽  
...  

SUMMARYAerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.


2000 ◽  
Vol 22 (7) ◽  
pp. 650-656 ◽  
Author(s):  
Hirohito Yano ◽  
Akira Hara ◽  
Katsunobu Takenaka ◽  
Kei Nakatanit ◽  
Jun Shinoda ◽  
...  

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Qianqing Wang ◽  
Xiangcui Guo ◽  
Li Li ◽  
Zhihui Gao ◽  
Xiaoke Su ◽  
...  

Abstract N6-methyladenosine (m6A) serves as the most common and conserved internal transcriptional modification. However, the roles of m6A on cervical cancer (CC) tumorigenesis are still unclear. Here, results indicated that METTL3 was significantly upregulated in CC tissue and cells, which was closely correlated with the lymph node metastasis and poor prognosis of CC patients. MeRIP-Seq analysis revealed the m6A profiles in CC cells. Functionally, METTL3 promoted the proliferation and Warburg effect (aerobic glycolysis) of CC cells. Mechanistically, METTL3 targeted the 3’-Untranslated Region (3’-UTR) of hexokinase 2 (HK2) mRNA. Moreover, METTL3 recruited YTHDF1, a m6A reader, to enhance HK2 stability. These findings demonstrated that METTL3 enhanced the HK2 stability through YTHDF1-mediated m6A modification, thereby promoting the Warburg effect of CC, which might promote a novel insight for the CC treatment.


2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i1-i2
Author(s):  
Celine Taglang ◽  
Georgios Batsios ◽  
Meryssa Tran ◽  
Anne Marie Gillepsie ◽  
Hema Artee Luchman ◽  
...  

Abstract The Warburg effect, characterized by elevated glucose uptake and flux to lactate, is a metabolic hallmark of cancer. Recent studies have identified deuterium 2H-magnetic resonance spectroscopy (MRS) using 6,6’-2H-glucose as a novel method of imaging the Warburg effect in high-grade primary glioblastomas (GBMs). However, its utility for imaging low-grade gliomas has not been tested. The goal of this study was to determine whether 6,6’-2H-glucose can be used for imaging tumor burden and treatment response in mutant isocitrate dehydrogenase (IDHmut) low-grade gliomas in vivo. We examined mice bearing orthotopic tumors of the patient-derived BT257 astrocytoma model. 1H-MRS, providing a readout of steady-state metabolite levels, confirmed the presence of 2-hydroxyglutarate, the product of IDHmut, in BT257 tumor tissue but not normal brain. Previous studies comparing IDHmut gliomas with GBMs suggest that IDHmut gliomas undergo lactate dehydrogenase silencing, potentially leading to a non-glycolytic phenotype. Nevertheless, our results indicated that, compared to normal brain, glucose uptake and concomitant flux to lactate were significantly higher in BT257 tumor tissue. Importantly, 6,6’-2H-glucose metabolism to lactate was observed in BT257 tumor-bearing mice, but not tumor-free mice. Furthermore, imaging studies confirmed spatial localization of lactate production to the tumor vs. contralateral normal brain. We then examined the ability of 6,6’-2H-glucose to assess treatment response. Poly-(adenosine 5′-diphosphate-ribose) polymerase inhibitors (PARPi) inhibit IDHmut glioma growth and are in clinical trials for IDHmut glioma patients. Treatment with the PARPi niraparib reduced 6,6’-2H-glucose flux to lactate in BT257 tumor-bearing mice. Importantly, this reduction was observed at early time-points when no difference in tumor volume could be detected using anatomical imaging, pointing to the ability of 6,6’-2H-glucose to assess pseudoprogression. Collectively, our results suggest that IDHmut gliomas display a glycolytic phenotype amenable to non-invasive 2H-MRS-based imaging of tumor burden and treatment response.


1971 ◽  
Vol 18 (3) ◽  
pp. 248-256 ◽  
Author(s):  
Eiichi Tani ◽  
Toshio Ametani

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