Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea.
J Endocrinol. 2018 Jun;237(3):255-269. doi: 10.1530/JOE-17-0700. Epub 2018 Apr 10.
The steroid receptor coactivator (SRC)-1 isoform/estrogen receptor (ER)-β axis has an essential role in endometriosis progression. In this context, therefore, bufalin was employed as a 'tool compound' to evaluate inhibitors of SRC in alternative endometriosis treatment. Bufalin effectively suppressed the growth of primary human endometrial stroma cells isolated from endometriosis patients compared to women without endometriosis and immortalized human endometrial epithelial and stromal cells expressing the SRC-1 isoform compared to their parental cells , compared to the vehicle, bufalin treatment significantly suppressed the growth of endometriotic lesions in mice with surgically induced endometriosis because bufalin disrupted the functional axis of SRC-1 isoform/ERβ by increasing SRC-1 isoform protein stability, hyperactivating the transcriptional activity of the SRC-1 isoform and degrading the ERβ protein by proteasome 26S subunit, non-ATPase 2 in endometriotic lesions. Bufalin treatment elevated the apoptosis signaling in epithelial cells of endometriotic lesions. In stromal cells of endometriotic lesions, bufalin treatment increased the levels of pyroptosis markers (caspase 1 and the active form of interleukin 1β) and reduced proliferation. In addition, bufalin treatment increased the expression levels of endoplasmic reticulum-stress (ERS) markers (PKR-like ER kinase, protein disulfide isomerase and binding immunoglobulin) in endometriotic lesions. Collectively, the bufalin-induced disruption of the SRC-1 isoform/ERβ axis might induce apoptosis, pyroptosis and ERS signaling in endometriotic lesions, causing the suppression of endometriosis. Therefore, future generations of SRC-modulators could be employed as an alternative medical approach for endometriosis treatment.
甾体激素受体共激活剂（SRC）-1 同工型/雌激素受体（ER）-β 轴在子宫内膜异位症的进展中起着重要作用。因此，在这种情况下，巴弗洛内酯被用作“工具化合物”来评估 SRC 的抑制剂，以替代子宫内膜异位症的治疗方法。与没有子宫内膜异位症的女性相比，巴弗洛内酯有效地抑制了从子宫内膜异位症患者中分离出的原代人子宫内膜基质细胞的生长，与表达 SRC-1 同工型的永生化人子宫内膜上皮和基质细胞相比，与载体相比，巴弗洛内酯治疗显著抑制了手术诱导的子宫内膜异位症小鼠子宫内膜异位病变的生长，因为巴弗洛内酯通过增加 SRC-1 同工型蛋白稳定性、过度激活 SRC-1 同工型的转录活性以及通过蛋白酶体 26S 亚单位降解 ERβ 蛋白，破坏了 SRC-1 同工型/ERβ 功能轴，在子宫内膜异位病变中，非 ATP 酶 2。巴弗洛内酯治疗可提高上皮细胞中细胞凋亡信号。在子宫内膜异位病变的基质细胞中，巴弗洛内酯治疗增加了细胞焦亡标志物（半胱氨酸天冬氨酸蛋白酶 1 和白细胞介素 1β 的活性形式）的水平并减少了增殖。此外，巴弗洛内酯治疗增加了内质网应激（ERS）标志物（PKR 样 ER 激酶、蛋白二硫键异构酶和结合免疫球蛋白）在子宫内膜异位病变中的表达水平。总之，巴弗洛内酯诱导的 SRC-1 同工型/ERβ 轴破坏可能会导致子宫内膜异位病变中的细胞凋亡、细胞焦亡和 ERS 信号转导，从而抑制子宫内膜异位症。因此，未来的 SRC 调节剂可以作为治疗子宫内膜异位症的替代医学方法。
