Endothelin (ET)-1 and ET-3 promote expression of c-fos and c-jun in human choriocarcinoma via ETB receptor-mediated Gi- and Gq-pathways and MAP kinase activation

Background and purpose: Endothelins (ETs) and their G protein-coupled receptors exert key physiological functions during normal and aberrant placental development. Trophoblast cells mediate the contact between the embryo and the mother, by establishing a transient organ, the placenta. Choriocarcinoma cells display many of the biochemical and morphological characteristics of in utero invasive trophoblast cells and may therefore be used as a suitable model to study epithelial tumour progression of foetal-derived cells. Experimental approach: The present study aimed at investigating ET receptor-mediated activation of the mitogen-activated protein kinase ( MAPK) pathway in human choriocarcinoma. Key results: Both JAR and Jeg-3 choriocarcinoma cell lines expressed ET receptor subtype B (ETB) but not ETA receptor transcripts. ETB receptor engagement by ET-1 and ET-3 resulted in a similar time-and concentration-dependent phosphorylation of p42/44 MAPK, also known as extracellular regulated kinase 1/2. Using specific pharmacological antagonists/inhibitors, we showed that ET-1/-3-mediated signal transduction by the ETB receptor is transmitted via G(i)- and G(q)-dependent pathways through activation of the Src (G(i)) and protein kinase C (G(q)) axis that converge at Ras/Raf, leading to downstream activation of p42/44. On a functional level, ETB engagement and subsequent phosphorylation of p42/44 resulted in enhanced transcription of the immediate early response genes c-fos and c-jun, a process commonly assumed to be mediated by the ETA receptor, and increased cell growth and relative cell area. Conclusions and implications: As human choriocarcinoma cells secrete ETs, pharmacological antagonism of ETs and/or ETB receptor-mediated signal transduction could represent a likely target therapy for choriocarcinoma.