Abstract
Glioma is the most common malignant tumor of the central nervous system. The urea cycle (UC) is an essential pathway to convert excess nitrogen and ammonia into the less toxic urea in humans. However, less is known about the functional significance of the urea cycle in glioma. p53 functions as a tumor suppressor and modulates several cellular functions and disease processes. In the present study, we aimed to explore whether p53 influences glioma progression by regulating the urea cycle. Here, we demonstrated the inhibitory impact of p53 on the expression of urea cycle enzymes and urea genesis in glioma cells. The level of polyamine, a urea cycle metabolite, was also regulated by p53 in glioma cells. Carbamoyl phosphate synthetase-1 (CPS1) is the first key enzyme involved in the urea cycle. Functionally, we demonstrated that CPS1 knockdown suppressed glioma cell proliferation, migration and invasion. Mechanistically, we demonstrated that the expression of ornithine decarboxylase (ODC), which determines the generation of polyamine, was regulated by CPS1. In addition, the impacts of p53 knockdown on ODC expression, glioma cell growth and aggressive phenotypes were significantly reversed by CPS1 inhibition. In conclusion, these results demonstrated that p53 inhibits polyamine metabolism by suppressing the urea cycle, which inhibits glioma progression.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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This work was supported by the Natural Science Foundation of Chongqing Science and Technology Bureau (Grant/award No: #cstc2020jcyj-msxmX0387), Yuzhong Science and Technology Bureau of Chongqing (Grant/award No: #2020115).
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In our research, Yuhong Zhao conducted the experiments and wrote the paper. Yingxi Chen and Ling Wei assisted with the experiments and data analysis. Jianhua Ran, Kejian Wang, Shujuan Zhu gave advice for experimental design. Qian Liu designed the experiments and revised the manuscript. All authors approved the final manuscript.
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Zhao, Y., Chen, Y., Wei, L. et al. p53 inhibits the Urea cycle and represses polyamine biosynthesis in glioma cell lines. Metab Brain Dis 38, 1143–1153 (2023). https://doi.org/10.1007/s11011-023-01173-y
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DOI: https://doi.org/10.1007/s11011-023-01173-y