Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.
Animals
Antineoplastic Agents
/ chemical synthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Colonic Neoplasms
/ drug therapy
DNA Damage
DNA Glycosylases
/ antagonists & inhibitors
DNA Repair
/ drug effects
DNA Replication
/ drug effects
DNA, Neoplasm
/ genetics
Enzyme Inhibitors
/ chemical synthesis
Gene Expression Regulation, Neoplastic
Guanine
/ analogs & derivatives
HCT116 Cells
Humans
Mice
Mice, Nude
Molecular Targeted Therapy
Oxidative Stress
Poly (ADP-Ribose) Polymerase-1
/ immunology
RNA, Small Interfering
/ genetics
Reactive Oxygen Species
/ antagonists & inhibitors
Signal Transduction
Survival Analysis
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
02 12 2020
02 12 2020
Historique:
accepted:
28
10
2020
revised:
15
10
2020
received:
28
02
2020
pubmed:
20
11
2020
medline:
30
12
2020
entrez:
19
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33211885
pii: 5992293
doi: 10.1093/nar/gkaa1048
pmc: PMC7708037
doi:
Substances chimiques
Antineoplastic Agents
0
DNA, Neoplasm
0
Enzyme Inhibitors
0
RNA, Small Interfering
0
Reactive Oxygen Species
0
8-hydroxyguanine
5614-64-2
Guanine
5Z93L87A1R
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
DNA Glycosylases
EC 3.2.2.-
oxoguanine glycosylase 1, human
EC 3.2.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12234-12251Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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