NRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted ImmunotherapiesReportar como inadecuado

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Oxidative Medicine and Cellular Longevity - Volume 2016 2016, Article ID 4148791, 22 pages -

Research Article

SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK

Pathology Division, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

Received 5 June 2015; Revised 23 August 2015; Accepted 25 August 2015

Academic Editor: Amit Tyagi

Copyright © 2016 Hilal S. Khalil et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.

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



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