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  2. MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos

MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos

  • Biochim Biophys Acta Mol Basis Dis. 2024 Apr 22;1870(5):167190. doi: 10.1016/j.bbadis.2024.167190.
Chunshuang Li 1 Yaoyao Xue 1 Jiaxin Wu 1 Lihong Zhang 1 Tianming Yang 1 Mengtao Ai 1 Jinling Han 1 Xu Zheng 1 Ruoxi Wang 2 Istvan Boldogh 3 Xueqing Ba 4
Affiliations

Affiliations

  • 1 The Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin 130024, China; School of Life Sciences, Northeast Normal University, Changchun, Jilin 130024, China.
  • 2 Key Laboratory of Animal Resistance Biology of Shandong Province, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, China.
  • 3 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
  • 4 The Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin 130024, China; School of Life Sciences, Northeast Normal University, Changchun, Jilin 130024, China. Electronic address: baxq755@nenu.edu.cn.
Abstract

Cervical Cancer cells possess high levels of Reactive Oxygen Species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical Cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair Enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical Cancer chemotherapy.

Keywords

MTH1 inhibition; OGG1; Oxidative DNA damage; Parthanatos; ROS-inducing agent.

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