Metabolic Regulation in Cancer Cell Dynamics and Applications

Cancer cells reprogram their metabolic networks to meet increased demands for energy, biosynthetic precursors and redox balance. Central to this rewiring is the shift towards aerobic glycolysis, known as the Warburg effect, which supports rapid ATP generation and provides intermediates for nucleotide and lipid synthesis. Beyond glycolysis, adaptations in the tricarboxylic acid (TCA) cycle, glutamine utilisation and the pentose phosphate pathway enable tumour cells to survive fluctuating nutrient and oxygen levels. Regulation occurs at multiple levels: altered expression or post-translational modification of rate-limiting enzymes; transcriptional control by oncogenic factors; and signalling pathways that sense cellular energy and stress. These mechanisms jointly influence proliferation, invasion and resistance to therapy. Recent advances have illuminated key metabolic nodes—such as the phosphofructokinase-1 platelet isoform and the bifunctional enzyme PFKFB3—offering novel targets. Therapeutic strategies include small-molecule inhibitors, combination regimens that exploit metabolic vulnerabilities and approaches to reverse metabolic plasticity, with promising preclinical outcomes and the potential for improved patient stratification in precision oncology.

Research from Nature Portfolio

Recent studies have elucidated how oncogenic signalling directly stabilises key glycolytic enzymes to drive tumour growth. One seminal investigation revealed that activation of a central growth kinase leads to phosphorylation of the platelet isoform of phosphofructokinase-1 (PFKP) at a specific serine residue, preventing its ubiquitin-mediated degradation. Enhanced PFKP stability increases glycolytic flux and promotes tumour proliferation in models of high-grade brain cancer. In parallel, work on epithelial–mesenchymal transition has shown that a major transcriptional repressor suppresses PFKP expression, diverting glucose into the pentose phosphate pathway. This switch generates NADPH for redox homeostasis and supports cancer cell survival under metabolic stress, while also potentiating metastasis.

Metabolic Regulation in Cancer Cell Dynamics and Applications publication trend

The graph below shows the total number of articles in metabolic regulation in cancer cell dynamics and applications across all publications each year (not limited to Nature Index journals).

Technical terms

Warburg effect: Preference of cancer cells for aerobic glycolysis over oxidative phosphorylation, even in oxygen-rich conditions.

PFKP: Platelet isoform of phosphofructokinase-1, a rate-limiting glycolytic enzyme whose stability is regulated by phosphorylation and ubiquitination.

PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, a bifunctional enzyme that synthesises fructose-2,6-bisphosphate to activate glycolysis.

Pentose phosphate pathway: Metabolic route branching from glycolysis that generates NADPH for anabolic reactions and ribose-5-phosphate for nucleotide synthesis.

c-Myc: Oncogenic transcription factor that up-regulates genes involved in glycolysis, nucleotide biosynthesis and cell growth, often forming feedback loops with metabolic enzymes.

References

1. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nature Communications (2017).
2. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nature Communications (2017).
3. A positive feedback loop between PFKP and c-Myc drives head and neck squamous cell carcinoma progression. Molecular Cancer (2024).
4. Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma. Journal of Experimental & Clinical Cancer Research (2017).