Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/12279
Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.
Visnes, Torkild | Benítez-Buelga, Carlos | Cázares-Körner, Armando | Sanjiv, Kumar | Hanna, Bishoy M F | Mortusewicz, Oliver | Rajagopal, Varshni | Albers, Julian J | Hagey, Daniel W | Bekkhus, Tove | Eshtad, Saeed | Baquero, Juan Miguel | Masuyer, Geoffrey | Wallner, Olov | Müller, Sarah | Pham, Therese | Göktürk, Camilla | Rasti, Azita | Suman, Sharda | Torres-Ruiz Raul, Torres-Ruiz Raul CNIO | Sarno, Antonio | Wiita, Elisée | Homan, Evert J | Karsten, Stella | Marimuthu, Karthick | Michel, Maurice | Koolmeister, Tobias | Scobie, Martin | Loseva, Olga | Almlöf, Ingrid | Unterlass, Judith Edda | Pettke, Aleksandra | Boström, Johan | Pandey, Monica | Gad, Helge | Herr, Patrick | Jemth, Ann-Sofie | El Andaloussi, Samir | Kalderén, Christina | Rodriguez-Perales, Sandra | Benítez, Javier | Krokan, Hans E | Altun, Mikael | Stenmark, Pål | Berglund, Ulrika Warpman | Helleday, Thomas | Rodriguez Perales, Sandra CNIO | El Andaloussi, Samir
Nucleic Acids Res . 2020 ;48(21):12234-12251.
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.
Gene Expression Regulation, Neoplastic | Animals | Antineoplastic Agents | Cell Line, Tumor | Cell Proliferation | Colonic Neoplasms | DNA Damage | DNA Glycosylases | DNA Repair | DNA Replication | DNA, Neoplasm | Enzyme Inhibitors | Guanine | HCT116 Cells | Humans | Mice | Mice, Nude | Molecular Targeted Therapy | Oxidative Stress | Poly (ADP-Ribose) Polymerase-1 | RNA, Small Interfering | Reactive Oxygen Species | Signal Transduction | Survival Analysis | Tumor Burden | Xenograft Model Antitumor Assays