Dysregulation of the urea cycle - potential targets for treatment and diagnosis in prostate cancer.

BACKGROUND

Prostate cancer (PCa) exhibits profound metabolic reprogramming, including dysregulation of the urea cycle (UC), an emerging driver of tumour growth, therapy resistance, and immune modulation. In normal physiology, the UC detoxifies ammonia via urea production. In PCa cells, however, altered expression of UC enzymes such as argininosuccinate synthase 1 (ASS1), arginase (ARG) and ornithine decarboxylase (ODC1) reroutes metabolites towards other pathways, including polyamine and nucleotide synthesis. These changes enhance proliferation, facilitate metabolic plasticity and influence the tumour microenvironment.

METHODS

This review summarises mechanistic insights into UC dysregulation in PCa, with emphasis on its interplay with the tricarboxylic acid (TCA) cycle, choline metabolism, and polyamine synthesis.

RESULTS

We critically evaluate current therapeutic strategies such as arginine deprivation (PEGylated arginine deiminase, ADI-PEG 20, PEGylated recombinant human arginase 1, PEG-BCT-100), ODC1 inhibition (α-difluoromethylornithine, DFMO), and glutaminase blockade (CB-839) and discuss their integration with other therapies, including androgen deprivation. Furthermore, we explore the challenges and the usefulness of UC metabolites as diagnostic and prognostic biomarkers for early detection of PCa as well as for a follow-up of patients during therapy.

CONCLUSIONS

We conclude that UC dysregulation represents a targetable metabolic vulnerability in PCa. However, successful translation will require combinatorial therapeutic approaches and rigorous validation of UC-based biomarkers in prospective clinical trials.