Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα)

Chia-Lung Tsai; Hsien-Ming Wu; Chiao-Yun Lin; Yi-Jun Lin; Angel Chao; Tzu-Hao Wang; Swei Hsueh; Chyong-Huey Lai; Hsin-Shih Wang

doi:10.1371/journal.pone.0072999

Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα)

PLoS One. 2013 Sep 9;8(9):e72999. doi: 10.1371/journal.pone.0072999. eCollection 2013.

Authors

Chia-Lung Tsai¹, Hsien-Ming Wu, Chiao-Yun Lin, Yi-Jun Lin, Angel Chao, Tzu-Hao Wang, Swei Hsueh, Chyong-Huey Lai, Hsin-Shih Wang

Affiliation

¹ Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Chang Gung University, Taoyuan, Taiwan ; Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Abstract

Estrogens and tamoxifen (an antiestrogen) exert their actions by activation of estrogen receptor (ER) through genomic and non-genomic mechanisms and are implicated in the development of endometrial cancer. Previous reports have demonstrated that estradiol and tamoxifen induce proliferation of human endometrial cancer cells through GPR30 (non-genomic ER) signaling pathway. Herein, we demonstrate that phosphorylation of focal adhesion kinase (FAK) is involved in cell migration induced by estradiol, tamoxifen and G1 (a GPR30 agonist) through the transmembrane ER (GPR30) in endometrial cancer cell lines with or without ERα (Ishikawa and RL95-2). Additionally, the GPR30-mediated cell migration was further abolished by administration of either specific RNA interference targeting GPR30 or an FAK inhibitor. Moreover, we have validated that the signaling between GPR30 and phosphorylated FAK is indeed mediated by the EGFR/PI3K/ERK pathway. Clinically, a significant correlation between levels of GPR30 and phophorylated FAK (pFAK) observed in human endometrial cancer tissues with low or without ERα further suggested that estrogen-induced phosphorylation of FAK and cell migration were most likely triggered by GPR30 activation. These results provided new insights for understanding the pathophysiological functions of GPR30 in human endometrial cancers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Movement / drug effects*
Cell Proliferation / drug effects
Endometrial Neoplasms / genetics
Endometrial Neoplasms / metabolism*
ErbB Receptors / metabolism
Estradiol / pharmacology*
Estrogen Receptor alpha / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Focal Adhesion Protein-Tyrosine Kinases / metabolism*
Gene Expression
Humans
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction / drug effects
Tamoxifen / pharmacology*
Tyrosine / metabolism
src-Family Kinases / metabolism

Substances

Estrogen Receptor alpha
GPER1 protein, human
Receptors, Estrogen
Receptors, G-Protein-Coupled
Tamoxifen
Tyrosine
Estradiol
Phosphatidylinositol 3-Kinases
ErbB Receptors
Focal Adhesion Protein-Tyrosine Kinases
src-Family Kinases
Extracellular Signal-Regulated MAP Kinases

Grants and funding

This work was supported by Grants NSC-96-2314-B-182-016 and NSC-97-2314-B-182-014-MY3 (to HSW) and NSC-99-2321-B-182A-003-MY3 (to CLT) from the National Science Council, Taiwan; and CMRPG381671 (to HMW) from Chang Gung Memorial Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.