Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
Visnes, T. (Sintef Industry. Department of Biotechnology and Nanomedicine)
Benítez-Buelga, Carlos (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Cázares-Körner, A. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Sanjiv, K. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Hanna, Bishoy (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Mortusewicz, O. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Rajagopal, Veera M (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Albers, J. J. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Hagey, D. W. (Karolinska Institutet (Estocolm, Suècia). Department of Laboratory Medicine)
Bekkhus, T. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Eshtad, S. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Baquero, Juan Miguel (Centro Nacional de Investigaciones Oncológicas)
Masuyer, G. (University of Bath. Department of Pharmacy and Pharmacology)
Wallner, O. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Müller, S. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Pham, T. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Göktürk, C. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Rasti, A. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Suman, S. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Torres, Raul (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Sarno, A. (Sintef Ocean. Department of Environment and New Resources)
Wiita, E. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Homan, E. J. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Karsten, S. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Marimuthu, K. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Michel, M. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Koolmeister, T. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Scobie, M. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Loseva, O. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Almlöf, I. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Unterlass, J. E. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Pettke, A. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Boström, J. (Karolinska Institutet (Estocolm, Suècia). Department of Laboratory Medicine)
Pandey, M. (University of Sheffield. Weston Park Cancer Centre)
Gad, H. (University of Sheffield. Weston Park Cancer Centre)
Herr, P. (University of Sheffield. Weston Park Cancer Centre)
Jemth, A. S. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
El Andaloussi, S. (Karolinska Institutet (Estocolm, Suècia). Department of Laboratory Medicine)
Kalderén, C. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Rodriguez-Perales, Sandra (Centro Nacional de Investigaciones Oncológicas)
Benítez, J. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Krokan, H. E. (Research and Innovation in Central Norway)
Altun, M. (Karolinska Institutet (Estocolm, Suècia). Department of Laboratory Medicine)
Stenmark, P. (Lund University. Department of Experimental Medical Science.)
Berglund, U. W. (Karolinska Institutet (Estocolm, Suècia). Department of Oncology and Pathology)
Helleday, Thomas (University of Sheffield.Weston Park Cancer Centre)
Universitat Autònoma de Barcelona

Date:	2021
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.
Grants:	Instituto de Salud Carlos III PI17-02303 Ministerio de Educación, Cultura y Deporte FPU15-01978 Instituto de Salud Carlos III PI16-00440
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Animals ; Antineoplastic Agents ; Cell Line, Tumor ; Cell Proliferation ; Colonic Neoplasms ; DNA Damage ; DNA Glycosylases ; DNA Repair ; DNA Replication ; DNA, Neoplasm ; Enzyme Inhibitors ; Gene Expression Regulation, Neoplastic ; Guanine ; HCT116 Cells ; Humans ; Mice ; Mice, Nude ; Molecular Targeted Therapy ; Oxidative Stress ; Poly (ADP-Ribose) Polymerase-1 ; Reactive Oxygen Species ; RNA, Small Interfering ; Signal Transduction ; Survival Analysis ; Tumor Burden ; Xenograft Model Antitumor Assays
Published in:	Nucleic acids research, Vol. 48 Núm. 21 (february 2021) , p. 12234-12251, ISSN 1362-4962

DOI: 10.1093/nar/gkaa1048
PMID: 33211885

18 p, 4.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Articles > Research articles
Articles > Published articles