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.
Highlights
The receptor tyrosine kinases (RTKs) are key drivers of normal cellular proliferation, differentiation, and survival, as well as determinants of cancer initiation, maintenance, and progression [1,2,3,4]
By generating gene transcriptional reporter assays, carrying out pharmacological activation or Small inhibitory RNA (SiRNA) knockdown of NF-E2 related factor-2 (NRF2), and performing HER2/HER3 functional inhibition and activation strategies, we have identified a direct node of functional integration of the two pathways in our ovarian cancer cell model which converges at NRF2
We found that pharmacological activation of NRF2 by tBHQ alone was sufficient to enhance the proliferation of both cell lines for six days (Figure 1)
Summary
The receptor tyrosine kinases (RTKs) are key drivers of normal cellular proliferation, differentiation, and survival, as well as determinants of cancer initiation, maintenance, and progression [1,2,3,4]. The phosphotyrosine residues serve as docking sites to recruit a number of signal adapter proteins containing the so-called SH2 and PTB domains, which link RTKs to different cellular signaling pathways such as PI3K/AKT/mTOR, MAPK, and STAT pathways [5, 6]. The HER receptor network contains four members (HER1, HER2, HER3, and HER4) whose activation kinetics depend significantly on their expression levels which vary across different cells and cancers [7]. Likewise it is these variations combined with receptor interaction that drive and confer complexity in the HER receptor family behaviour
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