TY  - JOUR
T1  - Nuclear factor erythroid 2-related factor 2 modulates HER4 receptor in ovarian cancer cells to influence their sensitivity to tyrosine kinase inhibitors
A1  - Kankia, Ibrahim H
A1  - Paramasivan, Poornima
A1  - Elcombe, Matthew
A1  - Langdon, Simon P
A1  - Yusuf, Y
Y1  - 2021///
KW  - Cancer
KW  - ovarian
KW  - nuclear factor erythroid 2-related factor 2
KW  - HER4-receptor
KW  - regulation
KW  - rexinoid
KW  - erlotinib
KW  - lapatinib
JF  - Exploration of Targeted Anti-tumor Therapy
SP  - 187
EP  - 203
UR  - https://www.explorationpub.com/Journals/etat/Article/100240
N2  - 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.
ER  -