NRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2018 Feb 8

PMID 29410730

Citations 18

Authors

Ibrahim H Kankia

Hilal S Khalil

Simon P Langdon

Peter R Moult

James L Bown

Yusuf Y Deeni

Affiliations

Soon will be listed here.

Abstract

NF-E2-related factor 2 (NRF2) regulates the transcription of a battery of metabolic and cytoprotective genes. NRF2 and epidermal growth factor receptors (EGFRs/HERs) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents. Nevertheless, there is limited understanding of the regulation of HER expression and activation and the link between NRF2 and HER signalling pathways. We show that NRF2 regulates both basal and inducible expression of , as treatment of ovarian cancer cells (PEO1, OVCAR3, and SKOV3) with NRF2 activator tBHQ inducing , while inhibition of NRF2 by siRNA knockdown or with retinoid represses . Furthermore, treatment of cells with tBHQ increased total and phosphorylated NRF2, HER1, and AKT levels and compromised the cytotoxic effect of lapatinib or erlotinib. Treatment with siRNA or retinoid antagonised the effect of tBHQ on NRF2 and HER1 levels and enhanced the sensitivity of ovarian cancer cells to lapatinib or erlotinib. Pharmacological or genetic inhibition of NRF2 and/or treatment with lapatinib or erlotinib elevated cellular ROS and depleted glutathione. This extends the understanding of NRF2 and its regulation of HER family receptors and opens a strategic target for improving cancer therapy.

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