Zearalenone promotes endometrial cancer cell migration and invasion via activation of estrogen receptor-mediated Rho/ROCK/PMLC signaling pathway

Zearalenone (ZEA), has emerged as a potential endocrine-disrupting chemical (EDC). Previous results show ZEA effects on endometrial stromal cell apoptosis, migration, and growth of endometriosis. Despite the reported presence of ZEA in Endometrial Cancer (EC) patient's blood and tissues, ZEA-induced EC promotion and its mechanism/s remain elusive. In this study, Ishikawa cells were used to investigate the ZEA effects on Ishikawa cell migration, invasion, and the underlying mechanism involved in these events. Ishikawa cells were exposed to low concentrations of ZEA (5, 25, and 125 nM) for 48 h, and morphological alterations, migration, invasion, markers associated with epithelial-mesenchymal transition (EMT), E-cadherin, Vimentin, RhoA/ROCK/PMLC pathway activation were analyzed. ZEA (25 nM) exposure caused morphological alterations like stress fiber, filopodia formation, loss of cell adhesion, and a significant increase in migration and invasive potential in extracellular matrix-coated porous membranes. Moreover, ZEA exposure also increases the Rho-GTPase activity and expression of pathway mediators, GEFH1, RhoA, ROCK1+2, CDC42, and PMLC/MLC. Furthermore, pre-treatment with specific pharmacological inhibitors for Estrogen receptor-alpha (ER-α) and ROCK attenuate the ZEA-induced stress fiber formation and altered expression of E-cadherin, Vimentin, and Rho/ROCK/PMLC pathway mediators. These findings suggest that Rho/ROCK/PMLC signaling pathways are involved in ZEA-induced Ishikawa cell migration and invasion.