Metabolic Pathways in Cancer Cell Proliferation

Cancer cells reprogramme their metabolism to support rapid proliferation, survival under stress and adaptation to fluctuating nutrient supplies. Central to this reprogramming is a shift towards aerobic glycolysis, known as the Warburg effect, which favours ATP generation and biosynthetic precursor production over complete oxidation of glucose. Concurrently, enhanced glutaminolysis supplies carbon and nitrogen for tricarboxylic acid (TCA) cycle anaplerosis, nucleotide and lipid biosynthesis. Alternative pathways such as the pentose phosphate pathway generate reducing equivalents (NADPH) for redox homeostasis and fatty acid synthesis, while reductive carboxylation of glutamine enables citrate formation in mitochondria-compromised conditions. Tumour hypoxia further drives metabolic flexibility, promoting the secretion of intermediates to avoid nitrogen accumulation and sustaining lipogenesis. Together, these interwoven pathways create metabolic vulnerabilities that can be exploited therapeutically, from targeting key enzymes to modulating nutrient availability in the tumour microenvironment.

Research from Nature Portfolio

Studies have revealed how hypoxic tumours coordinate glutamine carbon and nitrogen metabolism by channelling nitrogen into secreted dihydroorotate, ensuring safe disposal and simultaneous provisioning of acetyl-CoA for lipogenesis. This pathway is essential for tumour growth in vivo and explains how cancer cells maintain nucleotide synthesis and lipid production when oxygen is scarce.

Investigations into lymphoma have demonstrated that cooperative STAT3 and NF-κB signalling drives aberrant expression of glutamate oxaloacetate transaminase 2 (GOT2). GOT2 supplies aspartate and nucleotides under cytokine-stimulated conditions, linking microenvironmental cues to metabolic reprogramming. High GOT2 levels correlate with poor prognosis in diffuse large B-cell lymphoma, underscoring its potential as a biomarker and therapeutic target.

Metabolic Pathways in Cancer Cell Proliferation publication trend

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

Technical terms

Glycolysis: Cytosolic pathway converting glucose to pyruvate with net ATP and NADH production, supporting energy and biosynthesis in proliferating cells.

Glutaminolysis: Catabolic process whereby glutamine is deaminated to glutamate and further converted to α-ketoglutarate, fuelling the TCA cycle and providing nitrogen for nucleotide synthesis.

Oxidative phosphorylation: Mitochondrial generation of ATP via electron transfer through respiratory complexes and chemiosmotic coupling.

Pentose phosphate pathway: Alternative glucose catabolism route producing NADPH for reductive biosynthesis and ribose-5-phosphate for nucleotide assembly.

Anaplerosis: Replenishment of TCA cycle intermediates, often by amino acid or pyruvate carboxylation, to sustain biosynthetic fluxes.

Reductive carboxylation: Reverse TCA pathway step in which glutamine‐derived α-ketoglutarate is converted to isocitrate and citrate, supporting lipid synthesis under mitochondrial dysfunction.

References

1. Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches. Pharmaceutics (2022).
2. NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction. Molecular Cell (2018).
3. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia. Nature Communications (2019).
4. Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression. Nature Communications (2018).
5. Electron transport chain inhibition increases cellular dependence on purine transport and salvage. Cell Metabolism (2024).
6. Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells. Theranostics (2023).