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.
authors.affiliation: SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK.
authors.forename: Hilal S
authors.initials: HS
authors.lastname: Khalil
authors.affiliation: Pathology Division, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Kankia
authors.affiliation: SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bown
authors.affiliation: SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK.
authors.forename: Yusuf Y
authors.initials: YY
authors.lastname: Deeni
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D061745:Antioxidant Response Elements / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007167:Immunotherapy; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051547:Heme Oxygenase-1; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; D010768:Phosphoserine; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C495635:NFE2L2 protein, human; C018855:2-tert-butylhydroquinone; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C485206:pertuzumab