NRF2 regulates HER2 and HER3 signaling pathway to modulate sensitivity to targeted immunotherapies

Hilal S. Khalil, Simon P. Langdon, Ibrahim H. Kankia, James L. Bown, Yusuf Y. Deeni

    Research output: Contribution to journalArticle

    8 Citations (Scopus)
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    Abstract

    NF-E2 related factor-2 (NRF2) is an essential transcription factor for multiple genes encoding antioxidants and detoxification enzymes. NRF2 is implicated in promoting cancer therapeutic resistance by its detoxification function and crosstalk with proproliferative pathways. However, the exact mechanism of this intricate connectivity between NRF2 and growth factor induced proliferative pathway remains elusive. Here, we have demonstrated that pharmacological activation of NRF2 by tert-butylhydroquinone (tBHQ) upregulates the HER family receptors, HER2 and HER3 expression, elevates pAKT levels, and enhances the proliferation of ovarian cancer cells. Preactivation of NRF2 also attenuates the combined growth inhibitory effects of HER2 targeting monoclonal antibodies, Pertuzumab and Trastuzumab. Further, tBHQ caused transcriptional induction of HER2 and HER3, while SiRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression and enhanced cytotoxicity of the HER2 inhibitors. Hence, NRF2 regulates both HER2 and HER3 receptors to influence cellular responses to HER2 targeting monoclonal antibodies. This deciphered crosstalk mechanism reinforces the role of NRF2 in drug resistance and as a relevant anticancer target.
    Original languageEnglish
    Article number4148791
    Number of pages22
    JournalOxidative Medicine and Cellular Longevity
    Volume2106
    Early online date7 Dec 2015
    DOIs
    Publication statusPublished - Jan 2016

    Fingerprint

    NF-E2-Related Factor 2
    Immunotherapy
    Detoxification
    Crosstalk
    Monoclonal Antibodies
    Gene encoding
    Cytotoxicity
    Drug Resistance
    Ovarian Neoplasms
    Intercellular Signaling Peptides and Proteins
    Transcription Factors
    Up-Regulation
    Antioxidants
    Chemical activation
    Cells
    Pharmacology

    Cite this

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    title = "NRF2 regulates HER2 and HER3 signaling pathway to modulate sensitivity to targeted immunotherapies",
    abstract = "NF-E2 related factor-2 (NRF2) is an essential transcription factor for multiple genes encoding antioxidants and detoxification enzymes. NRF2 is implicated in promoting cancer therapeutic resistance by its detoxification function and crosstalk with proproliferative pathways. However, the exact mechanism of this intricate connectivity between NRF2 and growth factor induced proliferative pathway remains elusive. Here, we have demonstrated that pharmacological activation of NRF2 by tert-butylhydroquinone (tBHQ) upregulates the HER family receptors, HER2 and HER3 expression, elevates pAKT levels, and enhances the proliferation of ovarian cancer cells. Preactivation of NRF2 also attenuates the combined growth inhibitory effects of HER2 targeting monoclonal antibodies, Pertuzumab and Trastuzumab. Further, tBHQ caused transcriptional induction of HER2 and HER3, while SiRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression and enhanced cytotoxicity of the HER2 inhibitors. Hence, NRF2 regulates both HER2 and HER3 receptors to influence cellular responses to HER2 targeting monoclonal antibodies. This deciphered crosstalk mechanism reinforces the role of NRF2 in drug resistance and as a relevant anticancer target.",
    author = "Khalil, {Hilal S.} and Langdon, {Simon P.} and Kankia, {Ibrahim H.} and Bown, {James L.} and Deeni, {Yusuf Y.}",
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    NRF2 regulates HER2 and HER3 signaling pathway to modulate sensitivity to targeted immunotherapies. / Khalil, Hilal S.; Langdon, Simon P.; Kankia, Ibrahim H.; Bown, James L.; Deeni, Yusuf Y.

    In: Oxidative Medicine and Cellular Longevity, Vol. 2106, 4148791, 01.2016.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - NRF2 regulates HER2 and HER3 signaling pathway to modulate sensitivity to targeted immunotherapies

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    AU - Langdon, Simon P.

    AU - Kankia, Ibrahim H.

    AU - Bown, James L.

    AU - Deeni, Yusuf Y.

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    AB - NF-E2 related factor-2 (NRF2) is an essential transcription factor for multiple genes encoding antioxidants and detoxification enzymes. NRF2 is implicated in promoting cancer therapeutic resistance by its detoxification function and crosstalk with proproliferative pathways. However, the exact mechanism of this intricate connectivity between NRF2 and growth factor induced proliferative pathway remains elusive. Here, we have demonstrated that pharmacological activation of NRF2 by tert-butylhydroquinone (tBHQ) upregulates the HER family receptors, HER2 and HER3 expression, elevates pAKT levels, and enhances the proliferation of ovarian cancer cells. Preactivation of NRF2 also attenuates the combined growth inhibitory effects of HER2 targeting monoclonal antibodies, Pertuzumab and Trastuzumab. Further, tBHQ caused transcriptional induction of HER2 and HER3, while SiRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression and enhanced cytotoxicity of the HER2 inhibitors. Hence, NRF2 regulates both HER2 and HER3 receptors to influence cellular responses to HER2 targeting monoclonal antibodies. This deciphered crosstalk mechanism reinforces the role of NRF2 in drug resistance and as a relevant anticancer target.

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