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

TLDR

The Warburg effect, a preference for aerobic glycolysis in proliferating cells, is driven in glioblastoma multiforme by elevated hexokinase 2 expression, unlike normal brain and low‑grade gliomas that mainly express HK1. The study investigates the role of hexokinase 2 in sustaining the Warburg effect and promoting growth in human glioblastoma multiforme. HK2 overexpression in GBM correlates with poorer survival and drives proliferation, angiogenesis, and therapeutic resistance, while its depletion restores oxidative metabolism, sensitizes cells to radiation and temozolomide, reduces tumor growth and angiogenesis in xenografts, and suggests that targeting HK2 could impair GBM growth and enhance treatment response.

Abstract

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.