The 5-HT2A serotonin receptor enhances cell viability, affects cell cycle progression and activates MEK-ERK1/2 and JAK2-STAT3 signalling pathways in human choriocarcinoma cell lines

Previous results from our group have demonstrated the expression of the 5-HT2A receptor and a mitogenic effect of serotonin in human trophoblast. The objectives of the present study were to investigate the role of the 5-HT2A receptor in trophoblast cells and to determine the signalling pathways activated by this receptor. We investigated the effect of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), a selective 5-HT2A agonist, on cell cycle progression and cell viability in BeWo and JEG-3 cells. We also investigated, by co-immunoprecipitation and western blot analysis, the involvement of the MEK-ERK1/2 and JAK2-STAT3 signalling pathways following activation of the placental 5-HT2A receptor. Our results showed a concentration-dependent increase of cell viability by DOI, which was reversed by ketanserin, a selective 5-HT2A receptor antagonist. Furthermore, activation of the 5-HT2A receptor by DOI increased cell entry into the G2/M and S phase (DNA synthesis) in BeWo and JEG-3 cells, respectively. In addition, stimulation of BeWo and JEG-3 cells by DOI activated both the MEK-ERK1/2 and the JAK2-STAT3 signalling pathways. This study demonstrated that the 5-HT2A receptor increases cell viability and affects cell cycle progression in human trophoblast cell lines as well as activates the MEK-ERK1/2 and JAK2-STAT3 intracellular signalling pathways, which are related to survival, differentiation, migration and invasion. These findings indicate that serotonin through the activation of the 5-HT2A receptor is a key regulator of placentation and may play a role in the pathophysiology of certain pregnancy disorders associated with alterations in placental development, such as preeclampsia, gestational diabetes and preterm birth. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.