Please login first

Targeting OGG1 as a Novel Anti-Cancer Strategy
1 , 1, 2 , 1 , 1 , 1 , 1 , 3, 4 , 1 , 1 , 1 , 1 , 1 , 3, 5 , 1 , * 1, 6
1  Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
2  Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway
3  Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden
4  Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation. University of Bath, Bath BA2 7AY, UK
5  Department of Experimental Medical Science, Lund University, SE-221 00 Lund, Sweden
6  Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK

Abstract:

Due to oncogene expression and altered metabolism, reactive oxygen species (ROS) production is augmented in cancer cells resulting in oxidative DNA damage. 8‑oxoguanine (8-oxoG) is one of the most abundant oxidative DNA lesions. This premutagenic lesion is eliminated from duplex DNA by 8‑Oxoguanine DNA Glycosylase (OGG1), a key player in the base excision repair (BER) pathway. Here, we validate OGG1 as a potential anti-cancer target. OGG1 depletion impairs the growth of A3 T-cell lymphoblastic acute leukemia both in vitro and in vivo, but is well tolerated in non-transformed immortalized cells1. To further validate our findings, we developed TH5487, a potent small-molecule inhibitor that targets OGG1's active site [1,2]. We show that TH5487 suppresses the growth of a wide range of tumor cells, with a favorable therapeutic index compared to non‑transformed cells [1]. Mechanistically, TH5487 treatment inhibits the repair of potassium bromate-induced 8-oxo(d)G lesions, affects OGG1-chromatin dynamics, and hinders OGG1 recruitment to DNA damage regions [3]. Importantly, TH5487 induces replication stress and proliferation arrest1. This study presents a novel mechanistic strategy to exploit ROS elevation in cancer by inhibiting OGG1.

References:

  1. Visnes, T.; Benítez-Buelga, C.; Cázares-Körner, A.; Sanjiv, K.; Hanna, B.M.; Mortusewicz, O.; Rajagopal, V.; Albers, J.J.; Hagey, D.W.; Bekkhus, T. et al. Targeting OGG1 arrests cancer cell proliferation by inducing replication stress. Nucleic acids research 2020; 48, 12234–12251.
  2. Visnes, T.; Cázares-Körner, A.; Hao, W.; Wallner, O.; Masuyer, G.; Loseva, O.; Mortusewicz, O.; Wiita, E.; Sarno, A.; Manoilov, A. et al. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 2018, 362, 834–839.
  3. Hanna, B.M.F.; Helleday, T.; Mortusewicz, O. OGG1 inhibitor TH5487 alters OGG1 chromatin dynamics and prevents incisions. Biomolecules 2020, 10, 1–10.

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by approved by the regional experimental animal Ethical Committee in Stockholm 2010/63 (N8914)

Keywords: DNA damage response; oxidative DNA damage; base excision repair; OGG1 glycosylase; OGG1 inhibitor; TH5487; cancer; replication stress
Top