Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

Abstract

OBJECTIVE To determine the expression and biological roles of SGK1 in tissues and cells from patients with endometriosis and from healthy controls. DESIGN Case-control. SETTING University research setting. PATIENTS Premenopausal women. INTERVENTIONS Endometriotic tissues (E-Osis) were obtained from women with ovarian endometriosis and normal endometrial tissues (NoEM) were obtained from women undergoing hysterectomy for benign conditions. MAIN OUTCOMES MEASURES Expression levels of serum and glucocorticoid regulated kinase (SGK1), the role of SGK1 in E-Osis pathology, and the regulation of SGK1 by ERβ. RESULTS Transcript and protein levels of SGK1 were significantly higher in endometriotic tissues and cells compared to normal endometrium. SGK1 mRNA and protein levels were stimulated by estradiol, by the ERβ-selective agonist, diarylpropionitrile, and by prostaglandin E2. SGK1 was transcriptionally regulated by ERβ based on siRNA knockdown and chromatin immunoprecipitation of ERβ followed by quantitative PCR (ChIP-qPCR). SGK1 knockdown led to increased cleavage of PARP, and SGK1 activation was correlated with the phosphorylation of FOXO3a, a pro-apoptotic factor. CONCLUSIONS ERβ leads to SGK1 overexpression in endometriosis, which contributes to the survival of endometriotic lesions through inhibition of apoptosis.

Reversal of fortune: estrogen receptor-β in endometriosis

“…Taken together, these novel findings identify TNF-α-induced apoptosis as a key regulatory pathway disrupted by cytoplasmic-based ERβ to promote lesion survival. The cytoplasmic-localized ERβ anti-apoptotic action likely occurs in conjunction with nuclear-localized ERβ transcriptional activation of gene targets such as the serum and glucocorticoid-regulated kinase, which by phosphorylating the pro-apoptotic FOXO3, inhibits apoptosis (Monsivais et al ., 2016). However, the relative contribution of nuclear vs. cytoplasmic actions of ERβ to lesion survival is unknown.…”

Involvement of serum glucocorticoid‐regulated kinase 1 in reproductive success

“…Both of these steroid ovarian hormones stimulate SGK1 mRNA and protein levels in the human endometrium (23, 24). Abundance of SGK1 transcripts is significantly elevated and sustained throughout the secretory phase in the cycling human endometrium (25).…”

“…Indeed, by releasing trypsin, developmentally competent human embryos elicit short‐lived oscillatory Ca 2+ in endometrial epithelial cells, whereas low‐quality embryos trigger heightened and prolonged Ca 2+ fluxes (40). Of interest, a recent study conducted on human endometriotic tissues showed that prostaglandin E2 induced SGK1 expression significantly (24). Moreover, SGK1 ‐as an upstream kinase of ENaC‐regulates Na + signaling in different cells by altering the expression of this Na + channel (41, 42), which enhances ENaC open probability (43), attenuates its degradation, and promotes its trafficking (44).…”

“…This subcellular relocalization of FOXO1 from the nucleus to the cytosol abrogates its transcriptional activity, which results in promotion of cell differentiation (56). Moreover, another member of the FOXO subfamily, FOXO3a, is also a direct target of SGK1 (24, 57, 58), being phosphorylated by SGK1 at Thr32 and Ser315 (59). Like FOXO1, FOXO3a acts as a stabilizer of the differentiated state in nonproliferating cells, and both FOXOs have been implicated in human stromal cell decidualization (60).…”

Aromatase, microRNA, and inflammation: a complex relationship

“…2 Interestingly, pelvic endometriotic tissue responds to the biologically active estrogen, estradiol, in an exquisitely sensitive fashion possibly primarily through estrogen receptor-β (ERβ) via activation of specific kinases and stimulation of inflammatory pathways in endometriotic stromal cells. 3 …”