Differential actions of estrogen and SERMs in regulation of the actin cytoskeleton of endometrial cells

Abstract

Estrogen and selective estrogen receptor modulators (SERMs) differentially impact endometrial cell function, however, the biological basis of these differences is not established. Deregulated cell adhesion to the extracellular matrix, cell movement and invasion are related to endometrial disorders, such as endometriosis or endometrial cancer. Remodeling of the actin cytoskeleton is required to achieve cell adhesion and movement. Estrogen receptor (ER) regulates actin and cell membrane remodeling through extra-nuclear signaling cascades. In this article, we show that administration of 17beta-estradiol (E2) and tamoxifen (TAM) to immortalized Ishikawa endometrial cells or to human endometrial stromal cells (ESC) results in remodeling of actin fibers and cell membrane. This is linked to rapid phosphorylation on Thr(558) of the actin-binding protein moesin and enhanced migration and invasion of normal and Ishikawa cells. Raloxifene (RAL) does not result in moesin activation or actin remodeling. When endometrial cells are exposed to E2 in the presence of TAM or RAL, both SERMs interfere with the recruitment of moesin, with the remodeling of the cytoskeleton, and with cell movement and migration induced by E2. The differential actions of E2, TAM and RAL are linked to a distinct modulation of the extra-nuclear signaling of ER to G proteins and to the Rho-associated kinase. These findings increase our understanding of the actions of estrogen and SERMs in endometrial cells and highlight potential molecular targets to interfere with the estrogen-related altered cell adhesion encountered in endometrial disorders.

2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines

“…Moesin is constitutively activated by phosphorylation of threonine 555 [20] and the activation of ERM family members links actin filaments to CD43, CD44, and ICAM-1 which are involved in adhesion [21]. Moesin is critical for invasion in 3D matrices [22], and phosphorylation of moesin has also been linked with invasion in endometrial cells [23]. The alterations in MSN and RDX, observed in the dasatinib-treated WM-115 cells, may play a role in the effects of dasatinib on migration and invasion.…”

Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells

“…The effects of estradiol (E 2 ) on reproductive tract structure and function are well known. Recently, however, studies have indicated a role for E 2 in tumor initiation and progression through its promotion of the proliferative, migratory and invasive capabilities of cells (2)(3)(4)(5)(6). Many of the changes that occur in the endometrium during tumorigenesis are similar to those observed during implantation.…”

Estrogen regulates endometrial cell cytoskeletal remodeling and motility via focal adhesion kinase

“…Estrogens regulate several cytoskeletal components, particularly actin fibers (9)(10)(11). Through the control of actin organization, E regulates cell morphology and interaction with ECM and drives cell movement (9)(10)(11).…”

“…Through the control of actin organization, E regulates cell morphology and interaction with ECM and drives cell movement (9)(10)(11).…”