Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.
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.
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada.
Amparo
A
Wolf
Sameer
S
Agnihotri
Johann
J
Micallef
Joydeep
J
Mukherjee
Nesrin
N
Sabha
Rob
R
Cairns
Cynthia
C
Hawkins
Abhijit
A
Guha
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism* / Q000503:physiopathology; D006019:Glycolysis / Q000502:physiology*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D003606:Dacarbazine; D006593:Hexokinase; D000077204:Temozolomide
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