Uridine homeostatic disorder leads to DNA damage and tumorigenesis

Cancer Letters
Zhe CaoDeliang Cao

Abstract

Uridine is a natural nucleoside precursor of uridine monophosphate in organisms and thus is considered to be safe and is used in a wide range of clinical settings. The far-reaching effects of pharmacological uridine have long been neglected. Here, we report that the homeostatic disorder of uridine is carcinogenic. Targeted disruption (-/-) of murine uridine phosphorylase (UPase) disrupted the homeostasis of uridine and increased spontaneous tumorigenesis by more than 3-fold. Multiple tumors (e.g., lymphoma, hepatoma and lung adenoma) occurred simultaneously in some UPase deficient mice, but not in wild-type mice raised under the same conditions. In the tissue from UPase -/- mice, the 2'-deoxyuridine,5'-triphosphate (dUTP) levels and uracil DNA were increased and p53 was activated with an increased phospho-Ser18 p53 level. Exposing cell lines (e.g., MCF-7, RKO, HCT-8 and NCI-H460) to uridine (10 or 30 µM) led to uracil DNA damage and p53 activation, which in turn triggered the DNA damage response. In these cells, phospho-ATM, phospho-CHK2, and phospho-γH2AX were increased by uridine. These data suggest that uridine homeostatic disorder leads to uracil DNA damage and that pharmacological uridine may be carcinogenic.

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Citations

Oct 25, 2016·Cancer Letters·Yiwen BuDeliang Cao
Mar 25, 2017·International Journal of Oncology·Yu CaoDeliang Cao
Jun 30, 2018·Current Developments in Nutrition·Martha S FieldPatrick J Stover
Apr 9, 2020·Biomolecules·Irina A Il'ichevaSergey N Mikhailov
Dec 19, 2018·Proceedings of the National Academy of Sciences of the United States of America·Chenglong SunZeper Abliz
Jun 19, 2019·Journal of Lipid Research·Jan-Bernd Funcke, Philipp E Scherer
Sep 28, 2021·Journal of Animal Physiology and Animal Nutrition·Lewei GuoJun Wang

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