RelB-activated GPX4 inhibits ferroptosis and confers tamoxifen resistance in breast cancer
Zhi Xu,
Xiumei Wang,
Wenbo Sun,
Fan Xu,
Hengyuan Kou,
Weizi Hu,
Yanyan Zhang,
Qin Jiang,
Jinhai Tang,
Yong Xu
Affiliations
Zhi Xu
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China; Phase 1 Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
Xiumei Wang
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China
Wenbo Sun
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China
Fan Xu
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Affiliated Cancer Hospital, Nanjing Medical University, 42 Baiziting Avenue, Nanjing, 210009, China
Hengyuan Kou
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China
Weizi Hu
Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China
Yanyan Zhang
Affiliated Cancer Hospital, Nanjing Medical University, 42 Baiziting Avenue, Nanjing, 210009, China
Qin Jiang
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Corresponding author. Nanjing Medical University, China.
Jinhai Tang
Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China; Corresponding author. Nanjing Medical University, China.
Yong Xu
Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China; Affiliated Cancer Hospital, Nanjing Medical University, 42 Baiziting Avenue, Nanjing, 210009, China; Corresponding author. Nanjing Medical University, China.
Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.
