NRF2 inhibition represses ErbB2 signaling in ovarian carcinoma cells: implications for tumor growth retardation and docetaxel sensitivity

Abstract

NF-E2-related factor 2 (NRF2) is a transcription factor that regulates the expression of various antioxidant and detoxifying enzymes. Although the benefit of NRF2 in cancer prevention is well established, its role in cancer pathobiology was recently discovered. In this study, the role of NRF2 in tumor growth and docetaxel sensitivity was investigated in ErbB2-overexpressing ovarian carcinoma SKOV3 cells. Interfering RNA-mediated stable inhibition of NRF2 in SKOV3 cells repressed NRF2 signaling, resulting in cell growth arrest at G(0)/G(1) phase and tumor growth retardation in mouse xenografts. Microarray analysis revealed that ErbB2 expression is substantially reduced in NRF2-inhibited SKOV3 and this was further confirmed by RT-PCR and immunoblot analysis. Repression of ErbB2 led to a decrease in phospho-AKT and enhanced p27 protein, reinforcing the effect of NRF2 knockdown on SKOV3 growth. Furthermore, NRF2 inhibition-mediated ErbB2 repression increases the sensitivity of these cells to docetaxel cytotoxicity and apoptosis. The linkage between NRF2 and ErbB2 was confirmed in the ErbB2-positive breast cancer cell line BT-474: NRF2 knockdown suppressed ErbB2 expression and enhanced docetaxel sensitivity. Our results provide insight into the coordinated regulation of signaling molecules responding to environmental stress and suggest that NRF2 modulation might be a therapeutic strategy to limit tumor growth and enhance sensitivity to taxane-based chemotherapy.