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.