Mol. Hum. Reprod. Advance Access originally published online on June 18, 2009
Molecular Human Reproduction 2009 15(10):675-685; doi:10.1093/molehr/gap045
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This article appears in the following Molecular Human Reproduction issue: Special Issue: Mechanisms of Endometriosis [View the issue table of contents]
Differential actions of estrogen and SERMs in regulation of the actin cytoskeleton of endometrial cells
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100 Pisa, Italy
1 Correspondence address. Tel: +39-050-553412; Fax: +39-050-553410; E-mail: t.simoncini{at}obgyn.med.unipi.it; Web site: http://www.med.unipi.it/mcgel
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 17β-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 Thr558 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.
Key words: actin cytoskeleton/endometrial cells/estrogen/moesin/SERMs
Submitted on April 23, 2009; resubmitted on May 27, 2009; accepted on June 10, 2009.