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

• Published in: Free radical biology & medicine 2012-05, Vol.52 (9), p.1773-1785
• Main Authors: Manandhar, Sarala, Choi, Bo-hyun, Jung, Kyeong-Ah, Ryoo, In-geun, Song, Mingu, Kang, Su Jin, Choi, Han-Gon, Kim, Jung-Ae, Park, Pil-Hoon, Kwak, Mi-Kyoung
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; antioxidants; apoptosis; Base Sequence; Breast cancer; breast neoplasms; carcinoma; Cell Division; cell growth; Cell Line, Tumor; chemotherapy; cytotoxicity; DNA Primers; Docetaxel; enzymes; ErbB2; Female; Free radicals; Glutathione - metabolism; growth arrest; growth retardation; Humans; Interfering RNA; Mice; microarray technology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - physiology; NRF2; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction - physiology; Taxoids - pharmacology; transcription factors; Xenograft Model Antitumor Assays
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.02.031

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 G0/G1 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. [Display omitted] ► A NRF2-knockdown stable ovarian carcinoma cell line, SKOV3, was established. ► NRF2 knockdown resulted in G0/G1 cell cycle arrest and tumor growth retardation in mouse xenografts. ► ErbB2 expression was decreased in SKOV3 and breast cancer BT-474 cells by NRF2 knockdown. ► Reduced ErbB2 expression in these cells was associated with docetaxel sensitization.