NRF2 regulates HER1 signaling pathway to modulate the sensitivity of ovarian cancer cells to lapatinib and erlotinib

Kankia, I. H., Khalil, H. S., Langdon, S. P., Moult, P. R., Bown, J. L. and Deeni, Y. Y. (2017) NRF2 regulates HER1 signaling pathway to modulate the sensitivity of ovarian cancer cells to lapatinib and erlotinib. Oxidative Medicine and Cellular Longevity, 2017, 1864578. (doi: 10.1155/2017/1864578) (PMID:29410730) (PMCID:PMC5749283)

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 HER1, as treatment of ovarian cancer cells (PEO1, OVCAR3, and SKOV3) with NRF2 activator tBHQ inducing HER1, while inhibition of NRF2 by siRNA knockdown or with retinoid represses HER1. 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.

• Item Type: Articles
• Additional Information: This work was supported by grants from The Northwood Trust, Breakthrough Breast Cancer, Scottish Funding Council (SRDG), and PhD studentship support to Ibrahim H. Kankia from the Nigerian Tertiary Education (TET) Funds.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Moult, Dr Peter
• Authors: Kankia, I. H., Khalil, H. S., Langdon, S. P., Moult, P. R., Bown, J. L., and Deeni, Y. Y.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Oxidative Medicine and Cellular Longevity
• Publisher: Hindawi Publishing Corporation
• ISSN: 1942-0900
• ISSN (Online): 1942-0994
• Copyright Holders: Copyright © 2017 Ibrahim H. Kankia et al.
• First Published: First published in Oxidative Medicine and Cellular Longevity 2017: 1864578
• Publisher Policy: Reproduced under a Creative Commons License