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.
Highlights
Nuclear factor erythroid 2-related factor 2 (NRF2) is a basic leucine zipper protein that regulates the cell’s defense to oxidative stress by activing transcription of batteries of anti-oxidant genes [1,2,3]
While tBHQ increased the levels of both phosphorylated-NRF2 and HER4 in PE01, OVCAR3 and SKOV3 cells, bexatorene and NRF2-target Small interfering RNA (siRNA) treatment decreased pNRF2 and total HER4 levels
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. 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
Summary
Nuclear factor erythroid 2-related factor 2 (NRF2) is a basic leucine zipper protein that regulates the cell’s defense to oxidative stress by activing transcription of batteries of anti-oxidant genes [1,2,3]. NRF2 degrades under normal and unstressed conditions, but in the presence of oxidative stress, it moves to the nucleus where it dimerises with macrophage activating factor (Maf) proteins, binds to antioxidant response elements (AREs) and initiates transcription of anti-oxidative genes [1, 3, 6, 7]. The human epidermal growth factor receptor 4 (HER4/erbB4) is a cell surface receptor and member of the epidermal growth factor receptor (EGFR) tyrosine kinase family. This receptor family play major roles in cancer growth and progression [11,12,13,14]. HER4 is activated by neuregulins, e.g., heregulin (H), whereupon it can either homodimerise or heterodimerise with any other member (EGFR, HER2 or HER3) of the HER receptor family
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