The proliferation of tumor cells is a central feature of tumor development, requiring a significant supply of nutrients primarily sourced from nitrogen and carbon to build cellular macromolecules. In contrast, the urea cycle, a pivotal metabolic pathway, plays a critical role not only in ammonia metabolism and nitrogen homeostasis but also in its close association with proliferating tumor cells. The observed dysregulation of the urea cycle is closely correlated with proliferation and migration of tumor cells, highlighting its pivotal role in tumor growth.

The urea cycle is often dysregulated in cancer and a cellular biochemical process is designed to eliminate excess ammonia. Research indicated that the accumulation of ammonia in the urea cycle directly inhibited tumor growth (Li et al., 2019). The deficiency of argininosuccinate lyase (ASL) results in ammonia accumulation. ASL encodes a polypeptide that forms a homotetramer and is a pivotal enzyme in the urea cycle. Its primary function is to catalyze the conversion of argininosuccinate to arginine, which plays a central role in arginine synthesis (Mori and Gotoh, 2004). Arginine, synthesized by ASL, serves as the foundational element for the production of nitric oxide (NO), polyamines, γ-aminobutyric acid, creatine, proline, and glutamate, which are essential components for cell proliferation (Arruabarrena-Aristorena et al., 2018, Gerner and Meyskens, 2004, Nagamani et al., 2012). Elevated expression of ASL is significantly correlated with unfavorable prognosis in colorectal cancer, hepatocellular carcinoma, and breast cancer (Huang et al., 2017, Huang et al., 2013, Huang et al., 2015, Karvelsson et al., 2021, Gong et al., 2019). Tumor cells can adapt to the environment and regulate biosynthesis by regulating the expression of enzymes involved in the urea cycle. Abnormalities in any enzyme in the urea cycle can lead to disease and even fatality.

TAp73 is a member of the p53 family with high sequence homology and structural similarity to tumor suppressor (Moll and Slade, 2004, Melino et al., 2002, Yang et al., 2002, Deyoung and Ellisen, 2007). TAp73 is generally expressed at higher levels than p53 in tumor cells and is rarely mutated (Wang et al., 2020, Li et al., 2018), indicating that TAp73 has a proliferation advantage for tumor cells (Logotheti et al., 2021). TAp73 activates PFKL (Phosphofructokinase, liver type), enhances the Warburg effect, and targets pentose phosphate pathway (PPP) enzymes, promoting tumor cell proliferation (Li et al., 2018, Du et al., 2013, Qiao et al., 2023). Thus, TAp73 may be a potential drug target for tumor cells with high expression. Nevertheless, comprehensive investigations are warranted to elucidate the precise mechanism by which TAp73 modulates the urea cycle and its role in proliferating tumor cells.

The aim of this study is to investigate the molecular mechanisms through which TAp73 regulates ASL expression in proliferating tumor cells, with a particular focus on TAp73's effect on the regulation of the urea cycle and its role in ammonia accumulation. By revealing the mechanism of TAp73 in tumor cells, this study is expected to provide an important theoretical basis and potential clinical application for the development of new strategies and targeted drugs for tumor therapy.