Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
Por:
Visnes, T, Benitez-Buelga, C, Cazares-Korner, A, Sanjiv, K, Hanna, BMF, Mortusewicz, O, Rajagopal, V, Albers, JJ, Hagey, DW, Bekkhus, T, Eshtad, S, Baquero, JM, Masuyer, G, Wallner, O, Muller, S, Pham, T, Gokturk, 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, Almlof, I, Unterlass, JE, Pettke, A, Bostrom, J, Pandey, M, Gad, H, Herr, P, Jemth, AS, El Andaloussi, S, Kalderen, C, Rodriguez-Perales, S, Benitez, J, Krokan, HE, Altun, M, Stenmark, P, Berglund, UW and Helleday, T
Publicada:
2 dic 2020
Resumen:
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.
Filiaciones:
Visnes, T:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway
Benitez-Buelga, C:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Cazares-Korner, A:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Sanjiv, K:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Hanna, BMF:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Mortusewicz, O:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Rajagopal, V:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Albers, JJ:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Hagey, DW:
Karolinska Inst, Dept Lab Med, Stockholm, Sweden
Bekkhus, T:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Eshtad, S:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Baquero, JM:
Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid, Spain
Masuyer, G:
Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden
Univ Bath, Ctr Therapeut Innovat, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
Wallner, O:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Muller, S:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Pham, T:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Gokturk, C:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Rasti, A:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Suman, S:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
:
Spanish Natl Canc Res Ctr CNIO, Mol Cytogenet Grp, Human Canc Genet Program, Madrid 28029, Spain
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Barcelona 08036, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08036, Spain
Sarno, A:
Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway
Liaison Comm Educ Res & Innovat Cent Norway, Trondheim, Norway
SINTEF Ocean, Dept Environm & New Resources, N-7010 Trondheim, Norway
Wiita, E:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Homan, EJ:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Karsten, S:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Marimuthu, K:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Michel, M:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Koolmeister, T:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Scobie, M:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Loseva, O:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Almlof, I:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Unterlass, JE:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Pettke, A:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Bostrom, J:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Karolinska Inst, Sci Life Lab, Div Clin Physiol, Dept Lab Med, Stockholm, Sweden
Pandey, M:
Univ Sheffield, Dept Oncol & Metab, Weston Park Canc Ctr, Sheffield S10 2RX, S Yorkshire, England
Gad, H:
Univ Sheffield, Dept Oncol & Metab, Weston Park Canc Ctr, Sheffield S10 2RX, S Yorkshire, England
Herr, P:
Univ Sheffield, Dept Oncol & Metab, Weston Park Canc Ctr, Sheffield S10 2RX, S Yorkshire, England
Jemth, AS:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
El Andaloussi, S:
Karolinska Inst, Dept Lab Med, Stockholm, Sweden
Kalderen, C:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Rodriguez-Perales, S:
Spanish Natl Canc Res Ctr CNIO, Mol Cytogenet Grp, Human Canc Genet Program, Madrid 28029, Spain
Benitez, J:
Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid, Spain
Spanish Network Rare Dis CIBERER, Madrid, Spain
Krokan, HE:
Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway
Liaison Comm Educ Res & Innovat Cent Norway, Trondheim, Norway
Altun, M:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Karolinska Inst, Sci Life Lab, Div Clin Physiol, Dept Lab Med, Stockholm, Sweden
Stenmark, P:
Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden
Lund Univ, Dept Expt Med Sci, SE-22100 Lund, Sweden
Berglund, UW:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Helleday, T:
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17176 Stockholm, Sweden
Univ Sheffield, Dept Oncol & Metab, Weston Park Canc Ctr, Sheffield S10 2RX, S Yorkshire, England
Green Published, Green Accepted, gold
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