2. Academic Validation
  3. 8-oxo-dGTP curbs tumor development via S phase arrest and AIF-mediated apoptosis

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

  • Free Radic Biol Med. 2023 Jan 12;196:53-64. doi: 10.1016/j.freeradbiomed.2023.01.012.
Jin Li 1,  He Zhang 2,  Zhen-He Wang 1,  Yun-Xuan Li 1,  Li-Qun Zhang 1,  Ju Cui 1,  Dan-Ni Li 3,  Zi-Hui Wang 4,  Qian Liu 4,  Zhen Liu 4,  Tomoo Iwakuma 5,  Jian-Ping Cai 6
Affiliations

Affiliations

  • 1 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
  • 2 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China.
  • 3 Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China.
  • 4 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China.
  • 5 Children's Mercy Research Institute, Kansas City, MO, 64108, USA.
  • 6 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China. Electronic address: [email protected].
PMID: 36640852 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.

Keywords

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

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