title: Uridine homeostatic disorder leads to DNA damage and tumorigenesis.
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.
authors.affiliation: College of Bioscience and Biotechnology, Hunan Agricultural University, Furong District, Changsha 410128, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Boping
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Cai
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: College of Bioscience and Biotechnology, Hunan Agricultural University, Furong District, Changsha 410128, China. Electronic address: xwzhang@hunan.edu.cn.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Bioscience and Biotechnology, Hunan Agricultural University, Furong District, Changsha 410128, China; Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, USA; Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Electronic address: dcao@siumed.edu.
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D061986:MCF-7 Cells; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D014498:Uracil / Q000378:metabolism; D014529:Uridine / Q000378:metabolism* / Q000633:toxicity; D014543:Uridine Phosphorylase / Q000172:deficiency / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014498:Uracil; D014543:Uridine Phosphorylase; D014529:Uridine
keywords: Carcinogenesis; UPase knockout; Uracil DNA damage; Uridine homeostasis; Uridine phosphorylase; p53