title: Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells.
abstract: Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear-cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific.
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), University of Abertay Dundee, Dundee DD1 1HG, United Kingdom. Electronic address: H.Khalil@abertay.ac.uk.
authors.forename: Hilal S
authors.initials: HS
authors.lastname: Khalil
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), University of Abertay Dundee, Dundee DD1 1HG, United Kingdom. Electronic address: a.goltsov@abertay.ac.uk.
authors.forename: Alexey
authors.initials: A
authors.lastname: Goltsov
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Electronic address: Simon.Langdon@ed.ac.uk.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY16 9TF, United Kingdom. Electronic address: david.harrison@st-andrews.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), University of Abertay Dundee, Dundee DD1 1HG, United Kingdom. Electronic address: J.Bown@abertay.ac.uk.
authors.forename: James
authors.initials: J
authors.lastname: Bown
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), University of Abertay Dundee, Dundee DD1 1HG, United Kingdom. Electronic address: y.deeni@abertay.ac.uk.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Deeni
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000493:pharmacokinetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008957:Models, Genetic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide
keywords: Mathematical modelling; NRF2 localisation; Oxidative stress; Proliferation; ROS