Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis

Abstract

Decidualization or the differentiation of endometrial stromal cells (eSCs) into secretory decidual cells is required for successful implantation and pregnancy in menstruating species. Endometriosis, a condition accompanied by chronic pelvic pain and infertility, is observed in humans and a few species that menstruate. Several studies report that endometriosis is accompanied by significantly compromised decidualization, and this may explain some of the associated infertility. Current pharmacologics treat symptoms of endometriosis but do not alter disease progression. Sampson’s theory of retrograde menstruation is the most commonly accepted mechanism that explains the delivery of menstrual tissues to the peritoneal cavity where most endometriosis lesions develop. However, the exact etiology of endometriosis remains unknown. Recent studies support that cellular senescence, a phenotype found in shed menstrual tissues, impairs decidualization. Additionally, a senolytic agent, quercetin, has been reported to improve female fertility and reduce endometriosis in pre-clinical models. We examined the effect of quercetin on decidualization and stromal cell function using cultured eSCs isolated from menstrual effluent obtained from healthy, unaffected controls and endometriosis patients. Quercetin significantly inhibits eSC proliferation and improves decidualization of eSCs obtained from both endometriosis patients and controls. Mechanistic studies using eSCs reveal that quercetin rapidly blocks AKT, ERK1/2, and PRAS40 phosphorylation and inhibits the production of IL-6 and MMP3, prominent products of the senescence-associated secretory phenotype (SASP). Additionally, quercetin promotes both p53 phosphorylation and total p53 protein levels in eSCs and this is accompanied by increased apoptosis and the loss of larger beta-galactosidase-expressing eSCs with a senescence phenotype. This is the first study to reveal that quercetin enhances decidualization via senolytic and pro-apoptotic activities downstream of AKT signaling in controls and patients with endometriosis. These results support further investigating quercetin as a treatment for endometriosis and associated infertility.