NRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies

Oxidative Medicine and Cellular Longevity
Hilal S KhalilYusuf Y Deeni

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 antica...Continue Reading

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Citations

Feb 8, 2018·Oxidative Medicine and Cellular Longevity·Ibrahim H KankiaYusuf Y Deeni
Jul 13, 2017·Oxidative Medicine and Cellular Longevity·Hanna-Riikka TeppoPeeter Karihtala
Jun 6, 2017·Biochemical and Biophysical Research Communications·Yun YangZhiwei Feng
Apr 24, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Abbas Pirpour TazehkandNasser Samadi
Dec 11, 2021··Chao ShenXinghua Liao

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Methods Mentioned

BETA
PCR
electrophoresis
transfection

Software Mentioned

Gelpro
Andor iQ Core
SPSS
ConSite
Andor Module iQ Core

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