ERα-NRF2 signaling axis promotes bicalutamide resistance in PCa

Background: Bicalutamide is a potent and specific non-steroidal anti-androgen widely used as a first-line clinical treatment for prostate cancer (PCa). Although patients initially show an effective response to bicalutamide treatment, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa (CRPC). Estrogen receptor alpha (ERα) is significantly increased in bicalutamide-resistant PCa cell lines. Here, we investigated the roles of the estrogen-ERα signaling pathway in bicalutamide-resistant PCa cells. Methods Bioinformatics analyzed the expression and the correlation of ERα and nuclear factor E2-related factor 2 (NRF2) in human clinical datasets and tissue samples. RT-PCR, Western blotting, and immunofluorescence staining were used to evaluate the expression of ERα, NRF2 and resistance-related genes in cells treated with bicalutamide. The estrogen response element presents on the NRF2 promoter and facilitation of ERα binding to the NRF2 promoter were validated by the chromatin immunoprecipitation assay. The sensitivity of PCa cells to bicalutamide was evaluated by the MTT assay. Results ERα and NRF2 expression was significantly increased and positively correlated in CRPC cells. E2 promoted the expression of ERα and NRF2. ERα antagonist tamoxifen inhibited the upregulation of NRF2 induced by bicalutamide treatment. ERα-induced estrogen effects promote the activation of NRF2 signaling pathway via binding to NRF2 promoter. Moreover, ERα-NRF2 signaling axis resensitized PCa cells to bicalutamide and enhanced cell invasion and migration. Conclusion ERα-mediated estrogen effects promote bicalutamide resistance in CRPC cells by directly regulating NRF2 expression. This study suggests the molecular mechanism of PCa resistance to bicalutamide.