Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

Hilal S. Khalil, Alexey Goltsov, Simon P. Langdon, David J. Harrison, James Bown, Yusuf Deeni

Research output: Contribution to journalArticle

12 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)12-30
Number of pages19
JournalJournal of Biotechnology
Volume202
Early online date5 Nov 2014
DOIs
Publication statusPublished - 20 May 2015

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Antioxidants
Chemical elements
Ovarian Neoplasms
Reactive Oxygen Species
Cells
Oxygen
Networks (circuits)
Chemical analysis
Cell Line
Oxidation-Reduction
Homeostasis
Systems Biology
Adaptive systems
Growth
Half-Life
Theoretical Models
Mathematical models
Molecules
Kinetics

Cite this

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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.",
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Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells. / Khalil, Hilal S.; Goltsov, Alexey; Langdon, Simon P.; Harrison, David J.; Bown, James; Deeni, Yusuf.

In: Journal of Biotechnology, Vol. 202, 20.05.2015, p. 12-30.

Research output: Contribution to journalArticle

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T1 - Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

AU - Khalil, Hilal S.

AU - Goltsov, Alexey

AU - Langdon, Simon P.

AU - Harrison, David J.

AU - Bown, James

AU - Deeni, Yusuf

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AB - 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.

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