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)
    52 Downloads (Pure)

    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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    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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