Nuclear factor erythroid 2-related factor 2 modulates HER4 receptor in ovarian cancer cells to influence their sensitivity to tyrosine kinase inhibitors

Ibrahim H Kankia; Poornima Paramasivan; Matthew Elcombe; Simon P Langdon; Yusuf Y Deeni

doi:10.37349/etat.2021.00040

Nuclear factor erythroid 2-related factor 2 modulates HER4 receptor in ovarian cancer cells to influence their sensitivity to tyrosine kinase inhibitors

Explor Target Antitumor Ther. 2021;2(2):187-203. doi: 10.37349/etat.2021.00040. Epub 2021 Apr 30.

Authors

Ibrahim H Kankia^{1

2}, Poornima Paramasivan¹, Matthew Elcombe¹, Simon P Langdon³, Yusuf Y Deeni^{1

4}

Affiliations

¹ Division of Health Sciences, School of Applied Sciences, Abertay University, Dundee DD1 1HG, UK.
² Department of Biochemistry, Faculty of Natural and Applied Sciences, Umaru Musa Yar'adua University, Katsina PMB 2218, Nigeria.
³ Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
⁴ Department of Microbiology and Biotechnology, Faculty of Science, Federal University Dutse, Dutse PMB 7156, Nigeria.

Abstract

Aim: Nuclear factor erythroid 2-related factor 2 (NRF2) is a key component in the cell's response to oxidative and electrophilic stress and is a transcription factor regulating the expression of a collection of anti-oxidative and cytoprotective genes. Human epidermal growth factor receptor 4 (HER4/erbB4) regulates growth and differentiation in many cancer types. Here, NRF2 and HER4 receptor interactions were investigated in a panel of ovarian cancer cell lines.

Methods: Pharmacological [tert-butylhydroquinone (tBHQ) and retinoid/rexinoid, bexarotene] and genetic [small interfering RNA (siRNA)] manipulations were used to activate or inhibit NRF2 function in the cell line panel (PE01, OVCAR3, SKOV3). Activity of the HER-targeted tyrosine kinase inhibitors, erlotinib (ERL) and lapatinib (LAP), was evaluated after NRF2 activation.

Results: While tBHQ increased the levels of both phosphorylated-NRF2 (pNRF2) and HER4 in PE01, OVCAR3 and SKOV3 cells, bexatorene and NRF2-target siRNA treatment decreased pNRF2 and total HER4 levels. The tBHQ-dependent pharmacological activation of NRF2 attenuated the therapeutic effectiveness of ERL and LAP. Analyses of gene expression data from a HER4 driven reporter system and in vitro or in vivo cancer models, support NRF2 regulation of HER4 expression.

Conclusions: These results support the presence of signaling interaction between the NRF2 and HER4 receptor pathways and suggest that intervention modulating this cross-talk could have anticancer therapeutic value.

Keywords: Cancer; HER4-receptor; erlotinib; lapatinib; nuclear factor erythroid 2-related factor 2; ovarian; regulation; rexinoid.