Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme
Open accessAbstract
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.
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Aerobic glycolysis is required for NPC proliferation.
“These results indicate that, as found in cancer cell lines (Fantin et al., 2006; Wolf et al., 2011), aerobic glycolysis is required for NPC proliferation.”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Wolf et al., 2011
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- Authors
- Wolf, A., Agnihotri, S., Micallef, J., Mukherjee, J., Sabha, N., Cairns, R., Hawkins, C., & Guha, A.
- Affiliations
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- Corresponding author
- Guha, Abhijit
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-01-17
- Volume
- 208
- Issue
- 2
- Pages
- 313-326
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3039857
- OpenAlex
- W2122816851
- Cited by
- 789
- References
- 39
- Citations by year
- 2026: 39 · 2025: 47 · 2024: 47 · 2023: 40 · 2022: 64 · 2021: 60 · 2020: 66 · 2019: 63 · 2018: 54 · 2017: 53 · 2016: 61 · 2015: 58 · 2014: 48 · 2013: 39 · 2012: 31
- FWCI
- 14.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- American Brain Tumor Association
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hexokinase 2, aerobic glycolysis, Warburg effect, glioblastoma, tumor growth, hexokinase 1, PKM2, glucose oxidation, Akt signaling, mitochondrial translocation, treatment resistance, radiosensitivity, temozolomide, angiogenesis, tumor invasion, hypoxia-inducible factor-1α, vascular endothelial growth factor, glucose phosphorylation, overall survival
- MeSH terms
- Temozolomide, Dacarbazine, Flow Cytometry, Fluorescent Antibody Technique, Glioblastoma, Glycolysis, Hexokinase, Humans, Immunohistochemistry, Neovascularization, Pathologic, Phosphorylation, Blotting, Western, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit
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