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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Category
Academic article
Abstract
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.
Client
  • SINTEF AS / 102020885
  • Research Council of Norway (RCN) / 303369
Language
English
Author(s)
  • Torkild Visnes
  • Carlos Benitez-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 Gokturk
  • Azita Rasti
  • Sharda Suman
  • Raúl Torres-Ruiz
  • Antonio Sarno
  • Elisée Wiita
  • Evert Homan
  • Stella Karsten
  • Karthick Marimuthu
  • M 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 Einar Krokan
  • Mikael Altun
  • Pål Stenmark
  • Ulrika Warpman Berglund
  • Thomas Helleday
Affiliation
  • SINTEF Industry / Biotechnology and Nanomedicine
  • Karolinska Institutet
  • Spanish National Cancer Research Centre
  • Stockholm University
  • University of Bath
  • University of Barcelona
  • Norwegian University of Science and Technology
  • Helse Midt-Norge
  • SINTEF Ocean / Miljø og nye ressurser
  • University of Sheffield
  • Centro de Investigación Biomédica en Red
  • Lund University
Year
Published in
Nucleic Acids Research
ISSN
0305-1048
Publisher
Oxford University Press
Volume
48
Issue
21
Page(s)
12234 - 12251