Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer

// Jinyou Liu 1, 5 , Suryavathi Viswanadhapalli 1 , Lauren Garcia 1 , Mei Zhou 1, 6 , Binoj C. Nair 1 , Edward Kost 1 , Rajeshwar Rao Tekmal 1 , Rong Li 2 , Manjeet K. Rao 3 , Tyler Curiel 4 , Ratna K. Vadlamudi 1 and Gangadhara R. Sareddy 1 1 Department of Obstetrics and Gynecology, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas, USA 2 Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas, USA 3 Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, Texas, USA 4 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA 5 Department of Oncology, Xiangya School of Medicine, Central South University, Hunan, P.R. China 6 Department of Gastroenterology, Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, P.R. China Correspondence to: Gangadhara R. Sareddy, email: sareddy@uthscsa.edu Ratna K. Vadlamudi, email: vadlamudi@uthscsa.edu Keywords: ovarian cancer, natural ERβ agonists, NF-κB Received: February 07, 2017 Accepted: April 28, 2017 Published: June 12, 2017 ABSTRACT 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 (ERβ). Emerging evidence suggests that ovarian cancer cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in ovarian cancer remains elusive. We tested the utility of two natural ERβ 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 ERβ ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERβ 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 ERβ agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERβ interacts with p65 subunit of NF-κB and ERβ overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERβ agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.