Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Torkild Visnes; Carlos Benítez-Buelga; Armando Cázares-Körner; Kumar Sanjiv; Bishoy M F Hanna; Oliver Mortusewicz; Varshni Rajagopal; Julian J Albers; Daniel W Hagey; Tove Bekkhus; Saeed Eshtad; Juan Miguel Baquero; Geoffrey Masuyer; Olov Wallner; Sarah Müller; Therese Pham; Camilla Göktürk; Azita Rasti; Sharda Suman; Raúl Torres-Ruiz; Antonio Sarno; Elisée Wiita; Evert J Homan; Stella Karsten; Karthick Marimuthu; Maurice Michel; Tobias Koolmeister; Martin Scobie; Olga Loseva; Ingrid Almlöf; Judith Edda Unterlass; Aleksandra Pettke; Johan Boström; Monica Pandey; Helge Gad; Patrick Herr; Ann-Sofie Jemth; Samir El Andaloussi; Christina Kalderén; Sandra Rodriguez-Perales; Javier Benítez; Hans E Krokan; Mikael Altun; Pål Stenmark; Ulrika Warpman Berglund; Thomas Helleday

doi:10.1093/nar/gkaa1048

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Nucleic Acids Res. 2020 Dec 2;48(21):12234-12251. doi: 10.1093/nar/gkaa1048.

Authors

Torkild Visnes^{1

2}, Carlos Benítez-Buelga¹, Armando Cázares-Körner¹, Kumar Sanjiv¹, Bishoy M F Hanna¹, Oliver Mortusewicz¹, Varshni Rajagopal¹, Julian J Albers¹, Daniel W Hagey³, Tove Bekkhus¹, Saeed Eshtad¹, Juan Miguel Baquero⁴, Geoffrey Masuyer^{5

6}, Olov Wallner¹, Sarah Müller¹, Therese Pham¹, Camilla Göktürk¹, Azita Rasti¹, Sharda Suman¹, Raúl Torres-Ruiz^{7

8}, Antonio Sarno^{9

10

11}, Elisée Wiita¹, Evert J Homan¹, Stella Karsten¹, Karthick Marimuthu¹, Maurice Michel¹, Tobias Koolmeister¹, Martin Scobie¹, Olga Loseva¹, Ingrid Almlöf¹, Judith Edda Unterlass¹, Aleksandra Pettke¹, Johan Boström^{1

12}, Monica Pandey¹³, Helge Gad¹³, Patrick Herr¹³, Ann-Sofie Jemth¹, Samir El Andaloussi³, Christina Kalderén¹, Sandra Rodriguez-Perales⁷, Javier Benítez^{4

14}, Hans E Krokan^{9

10}, Mikael Altun^{1

12}, Pål Stenmark^{5

15}, Ulrika Warpman Berglund¹, Thomas Helleday^{1

13}

Affiliations

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 Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵ Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.
⁶ Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation. University of Bath, Bath BA2 7AY, UK.
⁷ Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
⁸ Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona 08036, Spain.
⁹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ The Liaison Committee for Education, Research and Innovation in Central Norway, Trondheim, Norway.
¹¹ Department of Environment and New Resources, SINTEF Ocean, N-7010 Trondheim, Norway.
¹² Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³ Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.
¹⁴ Spanish Network on Rare Diseases (CIBERER), Madrid, Spain.
¹⁵ Department of Experimental Medical Science, Lund University, SE-221 00 Lund, Sweden.

Abstract

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / mortality
DNA Damage
DNA Glycosylases / antagonists & inhibitors
DNA Glycosylases / genetics*
DNA Glycosylases / metabolism
DNA Repair / drug effects
DNA Replication / drug effects
DNA, Neoplasm / genetics*
DNA, Neoplasm / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Gene Expression Regulation, Neoplastic*
Guanine / analogs & derivatives
Guanine / metabolism
HCT116 Cells
Humans
Mice
Mice, Nude
Molecular Targeted Therapy
Oxidative Stress
Poly (ADP-Ribose) Polymerase-1 / immunology*
Poly (ADP-Ribose) Polymerase-1 / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Signal Transduction
Survival Analysis
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
DNA, Neoplasm
Enzyme Inhibitors
RNA, Small Interfering
Reactive Oxygen Species
8-hydroxyguanine
Guanine
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
DNA Glycosylases
oxoguanine glycosylase 1, human