Quercetin inhibits proliferation of endometriosis regulating cyclin D1 and its target microRNAs in vitro and in vivo

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a major dietary flavonol found in diverse fruits and vegetables such as onions, cauliflower, apple skin, lettuce and chili peppers. In recent studies, quercetin is reported as a functional compound and shows a wide range of biological effects such as antioxidant, anti-inflammatory and antiangiogenic properties in obesity, diabetes, cardiovascular diseases and various cancers. However, to date, the therapeutic effect of quercetin on the progression of endometriosis, which is a common gynecological disease in reproductive-aged women and brings chronic pelvic pain and infertility, has not been examined in depth. Results of this study demonstrated that quercetin inhibited the proliferation and induced the cell cycle arrest in VK2/E6E7 and End1/E6E7 cells. Furthermore, it induced cell apoptosis with DNA fragmentation, loss of mitochondrial membrane potential and reactive oxygen species production. The effects accompanied down-regulation of ERK1/2, P38 MAPK and AKT signaling molecules. Additionally, the administration of quercetin indicated antiproliferative and anti-inflammatory effects on endometriosis autoimplanted mouse models. The mRNA expression of Ccnd1 significantly decreased in response to quercetin intraperitoneal injection when compared to that in vehicle-treated mice. The knockdown of CCND1 mRNA attenuated the proliferation with sub-G₀/G₁ cell cycle arrest and increased the apoptosis of VK2/E6E7 and End1/E6E7 cells. Furthermore, the treatment of quercetin induced miR-503-5p, miR-1283, miR-3714 and miR-6867-5p related to CCND1 in both cell lines and also stimulated miR-503-5p and miR-546 expression in the mouse model. Hence, quercetin may potentially act as a natural therapeutic to reduce and treat human endometriosis.