Hexokinase-Mediated Metabolic Regulation in Cancer Cells

The first step of glucose metabolism is catalysed by hexokinases, of which hexokinase 2 (HK2) is the predominant isoform co-opted by malignant cells. Overexpressed HK2 fuels aerobic glycolysis, often termed the Warburg effect, providing both ATP and biosynthetic precursors that sustain rapid proliferation. Beyond its enzymatic role, HK2 localises to the outer mitochondrial membrane, where it modulates apoptosis and interacts with signalling pathways including mTORC1 and AMPK. This dual biochemical and scaffolding function allows cancer cells to adapt dynamically to nutrient fluctuations and to evade cell death. Recent findings highlight HK2’s involvement in redox homeostasis, autophagy regulation and the stabilisation of oncogenic kinases at discrete contact points between mitochondria and the endoplasmic reticulum. Genetic or pharmacological disruption of HK2 attenuates tumour growth in multiple models and sensitises cells to metabolic stressors such as metformin or sorafenib, underscoring its therapeutic potential. Moreover, targeting HK2 subcellular localisation emerges as a promising strategy to impair both energy production and survival signalling in diverse tumour types.

Research from Nature Portfolio

Seminal work has demonstrated that genetic depletion of HK2 in hepatocellular carcinoma models markedly suppresses glycolytic flux to lactate while preserving tricarboxylic acid cycle activity. Loss of HK2 triggers a metabolic shift towards oxidative phosphorylation, increasing reliance on serine one-carbon metabolism and amplifying reactive oxygen species production. When combined with metformin, oxidative phosphorylation is inhibited, causing synergistic cell death and enhanced tumour suppression. This dual targeting also impairs mTORC1 signalling through an AMPK-independent mechanism, and co-administration with sorafenib further reduces tumour burden, illustrating the efficacy of metabolic co-inhibition strategies in vivo.

Hexokinase-Mediated Metabolic Regulation in Cancer Cells publication trend

The graph below shows the total number of articles in hexokinase-mediated metabolic regulation in cancer cells across all publications each year (not limited to Nature Index journals).

Technical terms

Hexokinase 2 (HK2): An isoform of hexokinase that catalyses the phosphorylation of glucose to glucose-6-phosphate and is frequently upregulated in cancer.

Aerobic glycolysis (Warburg effect): Metabolic reprogramming in which cancer cells preferentially convert glucose to lactate even in the presence of oxygen.

Oxidative phosphorylation: Mitochondrial process of ATP generation via electron transport and chemiosmosis.

Autophagy: Cellular degradation pathway that recycles cytoplasmic components through lysosomal-mediated digestion.

Apoptosis: Programmed cell death involving caspase activation and regulated dismantling of cellular structures.

mTORC1: A nutrient-sensing kinase complex that regulates cell growth and metabolism in response to environmental cues.

References

1. Hexokinase 2 confers radio-resistance in hepatocellular carcinoma by promoting autophagy-dependent degradation of AIMP2. Cell Death & Disease (2023).
2. CCT6A facilitates lung adenocarcinoma progression and glycolysis via STAT1/HK2 axis. Journal of Translational Medicine (2024).
3. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nature Communications (2018).
4. Mitochondrial Binding of Hexokinase II Inhibits Bax-induced Cytochrome c Release and Apoptosis*. Journal of Biological Chemistry (2001).
5. Mitochondrial Bound Hexokinase Activity as a Preventive Antioxidant Defense STEADY-STATE ADP FORMATION AS A REGULATORY MECHANISM OF MEMBRANE POTENTIAL AND REACTIVE OXYGEN SPECIES GENERATION IN MITOCHONDRIA*. Journal of Biological Chemistry (2004).
6. Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters. International Journal of Molecular Sciences (2021).