8-oxo-dGTP curbs tumor development via S phase arrest and AIF-mediated apoptosis.

Document Type

Article

Publication Date

2-20-2023

Identifier

DOI: 10.1016/j.freeradbiomed.2023.01.012

Abstract

Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1-knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1-knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development.

Journal Title

Free radical biology & medicine

Volume

196

First Page

53

Last Page

64

MeSH Keywords

Humans; Animals; Mice; Phosphoric Monoester Hydrolases; S Phase; Deoxyguanine Nucleotides; Neoplasms; DNA; Mice, Knockout; Apoptosis; DNA Repair Enzymes

Keywords

8-oxo-dGTP; 8-oxoGTP; MTH1; tumor inhibition; tumorigenesis

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