1. Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.
- Author
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Visnes T, Benítez-Buelga C, Cázares-Körner A, Sanjiv K, Hanna BMF, Mortusewicz O, Rajagopal V, Albers JJ, Hagey DW, Bekkhus T, Eshtad S, Baquero JM, Masuyer G, Wallner O, Müller S, Pham T, Göktürk C, Rasti A, Suman S, Torres-Ruiz R, Sarno A, Wiita E, Homan EJ, Karsten S, Marimuthu K, Michel M, Koolmeister T, Scobie M, Loseva O, Almlöf I, Unterlass JE, Pettke A, Boström J, Pandey M, Gad H, Herr P, Jemth AS, El Andaloussi S, Kalderén C, Rodriguez-Perales S, Benítez J, Krokan HE, Altun M, Stenmark P, Berglund UW, and Helleday T
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms mortality, DNA Damage, DNA Glycosylases antagonists & inhibitors, DNA Glycosylases metabolism, DNA Repair drug effects, DNA Replication drug effects, DNA, Neoplasm metabolism, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Guanine analogs & derivatives, Guanine metabolism, HCT116 Cells, Humans, Mice, Mice, Nude, Molecular Targeted Therapy, Oxidative Stress, 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, Colonic Neoplasms drug therapy, DNA Glycosylases genetics, DNA, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Poly (ADP-Ribose) Polymerase-1 immunology
- 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., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2020
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