Glucose Transport Mechanisms in Cancer Metabolism

Cancer cells rewire their metabolism to satisfy high energetic and biosynthetic demands, prominently by up-regulating glucose uptake. This is chiefly mediated by the facilitative glucose transporter (GLUT) family, comprising multiple isoforms with distinct kinetic properties and tissue distributions. Oncogenic signalling pathways and tumour microenvironmental factors such as hypoxia and lipid composition converge to alter both the expression and activity of GLUTs, thereby promoting aerobic glycolysis (the Warburg effect). Isoform-specific regulation involves transcriptional control by factors including hypoxia-inducible factor 1 and oncogenic RAS, as well as post-translational modulation via transporter trafficking between intracellular compartments and the plasma membrane. The resultant increase in glucose influx fuels glycolytic intermediates for macromolecular synthesis, supports redox balance and contributes to an acidic microenvironment that favours invasion and therapy resistance. Therapeutic strategies targeting glucose transport range from small-molecule inhibitors to modulation of membrane lipid composition, with potential to exploit tumour-specific metabolic vulnerabilities and improve clinical outcomes.

Research from Nature Portfolio

Recent studies have advanced our mechanistic understanding of GLUT function and highlighted targetable dependencies. One report has established a reconstituted-liposome assay enabling precise measurement of GLUT1–4 and GLUT5 kinetics, demonstrating that membrane lipid composition critically influences transporter affinity and turnover. A further investigation into triple-negative breast cancer revealed that selective pharmacological or genetic blockade of GLUT1 markedly impairs proliferation in RB1-positive models, defining an exploitable RB1–GLUT1 metabolic axis. Complementary work in lung squamous cell carcinoma has shown that elevated GLUT1 expression underpins a glycolytic phenotype correlating with high fluorodeoxyglucose uptake and poor prognosis, thereby identifying subtype-specific susceptibility to glycolytic inhibition.

Glucose Transport Mechanisms in Cancer Metabolism publication trend

The graph below shows the total number of articles in glucose transport mechanisms in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

GLUT (glucose transporter): A family of membrane proteins (SLC2A) facilitating passive hexose uptake across the plasma membrane.

Aerobic glycolysis: Metabolic programme in which glucose is preferentially converted to lactate in the presence of oxygen, supporting rapid proliferation.

KM (Michaelis constant): Substrate concentration at which a transporter or enzyme operates at half its maximal velocity, reflecting affinity.

Membrane fluidity: Physical state of lipid bilayers influencing protein mobility and function, affecting transporter kinetics.

Translocation: The regulated movement of transporters between intracellular compartments and the cell surface, modulating substrate uptake.

References

1. Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system. Nature Communications (2023).
2. GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer. Nature Communications (2020).
3. The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nature Communications (2017).
4. Tryptophan deficiency induced by indoleamine 2,3‐dioxygenase 1 results in glucose transporter 1‐dependent promotion of aerobic glycolysis in pancreatic cancer. MedComm (2024).
5. Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy. International Journal of Molecular Sciences (2019).
6. Regulation of glut1 mRNA by Hypoxia-inducible Factor-1 INTERACTION BETWEEN H-ras AND HYPOXIA*. Journal of Biological Chemistry (2000).