Arginine Metabolism in Cancer Therapy

Arginine plays a dual role in cancer biology as both a signalling metabolite that activates key pathways, notably mTOR, and as a precursor for nitric oxide, polyamines and other biosynthetic processes. In many tumours, transcriptional or epigenetic suppression of argininosuccinate synthase (ASS1) and argininosuccinate lyase (ASL) renders cells unable to synthesise arginine de novo, a phenomenon known as arginine auxotrophy. This metabolic vulnerability has been exploited therapeutically through the use of enzymatic agents such as pegylated arginine deiminase or recombinant arginase to deplete extracellular arginine, thereby starving cancer cells. Deprivation therapies have been combined with conventional chemotherapies and targeted agents to enhance cytotoxicity and overcome chemoresistance. Mechanistic studies reveal that arginine depletion can disrupt nucleotide synthesis, induce mitochondrial dysfunction via aspartate exhaustion and trigger cell death pathways including autophagy, apoptosis and necroptosis. Emerging strategies focus on modulating arginine uptake, restoring ASS1 expression and harnessing the tumour microenvironment to improve efficacy. Clinical trials continue to refine dosing regimens and combination protocols, underscoring the global significance of arginine-targeted approaches in precision oncology.

Research from Nature Portfolio

Recent studies have uncovered a central role for ASS1 in the DNA damage response of tumour cells. Loss of ASS1 not only diverts aspartate towards nucleotide synthesis, enhancing proliferation, but also compromises genome integrity by accelerating DNA damage. Following chemotherapeutic insult, ASS1 is upregulated in both cytosolic and nuclear compartments in a p53-dependent manner, where it restrains cell-cycle progression through nucleotide limitation and fumarate-mediated succination of chromatin remodelling factors. Separately, investigations into arginine starvation reveal that depletion of extracellular arginine in ASS1-deficient cells precipitates mitochondrial distress and transcriptional remodelling. Induction of asparagine synthetase under arginine deprivation depletes intracellular aspartate, disrupting the malate–aspartate shuttle and triggering cell death. Dietary arginine restriction in animal models of ASS1-deficient breast cancer has further validated these mechanistic insights and demonstrated antitumour efficacy in vivo.

Arginine Metabolism in Cancer Therapy publication trend

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

Technical terms

Arginine auxotrophy: A metabolic dependency of certain cancer cells on external arginine due to insufficient expression of the enzymes required for its synthesis.

Argininosuccinate synthase (ASS1): The rate-limiting enzyme of the urea cycle that catalyses the conversion of citrulline and aspartate to argininosuccinate.

Argininosuccinate lyase (ASL): An enzyme that converts argininosuccinate into arginine and fumarate in the final step of the urea cycle.

Arginine deiminase (ADI): An enzyme, often pegylated for therapy, that degrades arginine to citrulline and ammonia, used to starve arginine-auxotrophic tumour cells.

Asparagine synthetase (ASNS): The enzyme that catalyses the ATP-dependent conversion of aspartate to asparagine, thereby affecting aspartate availability.

Malate–aspartate shuttle: A biochemical system that transfers reducing equivalents across the mitochondrial membrane using malate and aspartate as carriers.

References

1. ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response. Nature Metabolism (2024).
2. Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia. Journal of Experimental & Clinical Cancer Research (2023).
3. Targeting RNA‐binding motif protein 39 for arginine reduction: unveiling metabolic vulnerability in arginine‐dependent liver cancer. MedComm (2024).
4. Arginine Signaling and Cancer Metabolism. Cancers (2021).
5. Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Communications Biology (2018).