RESUMO
Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERα) and estrogen receptor beta (ERß). Emerging evidence suggests that ovarian cancer cells express ERß that functions as a tumor suppressor; however, the clinical utility of ERß agonists in ovarian cancer remains elusive. We tested the utility of two natural ERß agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERß ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERß agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERß agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERß interacts with p65 subunit of NF-κB and ERß overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERß agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERß agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERß agonists represent novel therapeutic agents for the management of ovarian cancer.
