Aldolase Function and Glycolytic Pathways in Cancer Systems

Aldolase enzymes catalyse the reversible cleavage of fructose-1,6-bisphosphate in the fourth step of glycolysis, a pathway that is frequently upregulated in cancer cells to meet energetic and biosynthetic demands. Beyond their central metabolic role, aldolase isoforms engage in diverse ‘moonlighting’ activities, including scaffold formation, transcriptional regulation and signalling modulation. In tumours, the preferential use of aerobic glycolysis—commonly referred to as the Warburg effect—supports rapid proliferation, survival under hypoxia and resistance to therapy. Cancer cells exploit aldolase not only to sustain high glycolytic flux and lactate production but also to regulate gene expression programmes and DNA repair processes. Emerging evidence reveals that aldolase isoforms translocate to the nucleus, interact with key kinases, influence transcription factors and participate in non-metabolic functions that collectively drive tumour growth, metastasis and treatment resistance. Understanding these multifaceted roles offers new avenues for therapeutic intervention, including selective enzyme inhibition, disruption of protein–protein interactions and targeting of non-canonical aldolase functions to impair cancer cell viability and enhance sensitivity to existing treatments.

Research from Nature Portfolio

Recent studies have uncovered a direct role for aldolase A in the repair of DNA double-strand breaks. Upon genotoxic stress, aldolase A relocates from the cytosol into the nucleus and associates with the major repair kinases DNA-PK and ATM. Loss of aldolase A impairs both non-homologous end-joining and homologous recombination, slows repair kinetics and increases sensitivity to ionising radiation. Mechanistically, aldolase A facilitates autophosphorylation of repair kinases, thereby coordinating metabolic status with genome integrity. This dual functionality highlights a convergence between energy metabolism and DNA damage response pathways and suggests that inhibiting aldolase A could simultaneously disrupt cancer metabolism and DNA repair capacity.

Aldolase Function and Glycolytic Pathways in Cancer Systems publication trend

The graph below shows the total number of articles in aldolase function and glycolytic pathways in cancer systems across all publications each year (not limited to Nature Index journals).

Technical terms

Aldolase A (ALDOA): A glycolytic enzyme that cleaves fructose-1,6-bisphosphate and engages in non-metabolic interactions affecting transcription and DNA repair.

Glycolysis: A ten-step metabolic pathway converting glucose to pyruvate, generating ATP and biosynthetic precursors.

Warburg effect: The preferential utilisation of aerobic glycolysis by cancer cells, leading to high glucose uptake and lactate production despite oxygen availability.

Metabolic reprogramming: The alteration of cellular metabolism in cancer to support rapid growth, survival and adaptation to microenvironmental challenges.

Non-homologous end-joining (NHEJ) and homologous recombination (HR): Two principal pathways for repair of DNA double-strand breaks, essential for genome stability.

Moonlighting function: A non-canonical role of a protein distinct from its primary enzymatic activity, often involving interactions with other macromolecules or regulation of signalling pathways.

References

1. The fructose-bisphosphate, Aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair. Scientific Reports (2023).
2. Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms. Advanced Science (2023).
3. ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis. Journal of Experimental & Clinical Cancer Research (2023).
4. Aldolase A accelerates hepatocarcinogenesis by refactoring c-Jun transcription. Journal of Pharmaceutical Analysis (2024).