Liu Jinyou, Viswanadhapalli Suryavathi, Garcia Lauren, Zhou Mei, Nair Binoj C, Kost Edward, Rao Tekmal Rajeshwar, Li Rong, Rao Manjeet K, Curiel Tyler, Vadlamudi Ratna K, Sareddy Gangadhara R
Department of Obstetrics and Gynecology, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas, USA.
Department of Oncology, Xiangya School of Medicine, Central South University, Hunan, P.R. China.
Oncotarget. 2017 Jul 25;8(30):50002-50014. doi: 10.18632/oncotarget.18442.
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.
卵巢癌是所有妇科癌症中致死率最高的。尽管初始化疗取得了成功，但大多数患者会复发，且疾病无法治愈。化疗耐药性的产生是卵巢癌长期生存率低的一个主要因素。雌激素的生物学效应由雌激素受体α（ERα）和雌激素受体β（ERβ）介导。新出现的证据表明，卵巢癌细胞表达的ERβ具有肿瘤抑制功能；然而，ERβ激动剂在卵巢癌中的临床应用仍不明确。我们测试了两种天然ERβ激动剂甘草素（Liq）和S-雌马酚的效用，甘草素是从甘草中分离出来的，S-雌马酚是从大豆异黄酮大豆苷元中分离出来的，用于治疗卵巢癌。在细胞活力和生存试验中，这两种天然ERβ配体均具有显著的生长抑制作用，减少了迁移和侵袭，并促进了细胞凋亡。此外，ERβ激动剂在耐药性卵巢癌模型细胞中显示出肿瘤抑制功能，并使卵巢癌细胞对顺铂和紫杉醇治疗敏感。全基因组RNA测序分析表明，ERβ激动剂可调节多种肿瘤抑制途径，包括下调NF-κB途径。免疫沉淀试验表明，ERβ与NF-κB的p65亚基相互作用，ERβ的过表达降低了NF-κB靶基因的表达。在异种移植试验中，ERβ激动剂减少了肿瘤生长并促进了细胞凋亡。总的来说，我们的研究结果表明，天然ERβ激动剂有可能通过抗炎和促凋亡作用显著抑制卵巢癌细胞的生长，天然ERβ激动剂代表了用于治疗卵巢癌的新型治疗药物。
