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 - 2016

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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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journal = "Oxidative Medicine and Cellular Longevity",
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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, 2016.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - Khalil, Hilal S.

AU - Langdon, Simon P.

AU - Kankia, Ibrahim H.

AU - Bown, James L.

AU - Deeni, Yusuf Y.

PY - 2016

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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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