Folate Metabolism and Cellular Proliferation in Cancer

Folate metabolism underpins one-carbon transfer reactions that drive nucleotide synthesis, methylation reactions and redox balance in proliferating cells. Dietary folates are converted intracellularly into tetrahydrofolate (THF) derivatives that serve as carriers of one-carbon units, mediating the synthesis of purine and thymidine nucleotides and the remethylation of homocysteine. Cancer cells often upregulate folate-dependent pathways to meet heightened demands for nucleic acids and methyl groups, while downregulating enzymes that divert folate cofactors away from biosynthesis. One such enzyme, 10-formyltetrahydrofolate dehydrogenase (ALDH1L1), acts as a tumour suppressor by depleting formyl-THF and thereby restraining de novo purine synthesis. Loss or epigenetic silencing of ALDH1L1 is a common feature in many malignancies, facilitating metabolic reprogramming and unchecked proliferation. Emerging research also highlights connections between folate metabolism and mitochondrial function, redox homeostasis and sensitivity to chemotherapeutics. Together, these insights reveal folate pathways as integrators of cellular growth programmes and as promising targets for selective anticancer strategies.

Research from Nature Portfolio

Recent studies have elucidated how ALDH1L1 modulates mitochondrial metabolism in hepatocellular carcinoma. Re-expression of this enzyme in cell models reduced serine availability, increased glycine pools and led to accumulation of the purine intermediate ZMP, revealing a mechanistic link between formyl-THF consumption and mitochondrial oxidative phosphorylation. This work suggests that ZMP analogues may offer therapeutic benefit in tumours with ALDH1L1 loss. Complementary cryo-EM analyses of the tetrameric ALDH1L1 complex have resolved its dynamic domain architecture, showing how a carrier-like intermediate module transfers formyl groups between catalytic centres. The structural insights underscore the enzyme’s essential quaternary organisation for catalysis and highlight potential interfaces for small-molecule modulation.

Folate Metabolism and Cellular Proliferation in Cancer publication trend

The graph below shows the total number of articles in folate metabolism and cellular proliferation in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

One-carbon metabolism: Cellular network using folate derivatives to transfer single-carbon units for nucleotide and methyl group synthesis.

Tetrahydrofolate (THF): Active form of folate that accepts and donates one-carbon units in metabolic pathways.

10-Formyltetrahydrofolate dehydrogenase (ALDH1L1): Enzyme converting 10-formyl-THF to THF and CO₂, regulating folate pools and proliferation.

De novo purine synthesis (dnPS): Pathway constructing purine nucleotides from small precursors, reliant on folate-derived formyl groups.

5-Aminoimidazole-4-carboxamide ribonucleotide (ZMP): Intermediate in purine biosynthesis that accumulates when formyl group transfer is impeded.

References

1. Metabolomics Analysis Reveals Novel Targets of Chemosensitizing Polyphenols and Omega-3 Polyunsaturated Fatty Acids in Triple Negative Breast Cancer Cells. International Journal of Molecular Sciences (2023).
2. One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression. Scientific Reports (2023).
3. Structure of putative tumor suppressor ALDH1L1. Communications Biology (2022).
4. The Combination of Loss of ALDH1L1 Function and Phenformin Treatment Decreases Tumor Growth in KRAS-Driven Lung Cancer. Cancers (2020).
5. Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis. Cancers (2021).
6. Deep Sequencing Revealed a CpG Methylation Pattern Associated With ALDH1L1 Suppression in Breast Cancer. Frontiers in Genetics (2018).