Research Paper
Subject Category: Cancer Pharmacology
British Journal of Pharmacology (2008) 154, 13–24; doi:10.1038/bjp.2008.92; published online 24 March 2008
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
A Rauh1,4, W Windischhofer2,4, A Kovacevic1, T DeVaney3, E Huber2, M Semlitsch1, H-J Leis2, W Sattler1 and E Malle1
- 1Center of Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
- 2University Childrens Hospital, Research Unit of Osteological Research and Analytical Mass Spectrometry, Medical University of Graz, Graz, Austria
- 3Center of Physiological Medicine, Institute of Biophysics, Medical University of Graz, Graz, Austria
Correspondence: Dr E Malle, Center of Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz A-8010, Austria. E-mail: ernst.malle@meduni-graz.at
4These authors contributed equally to this work.
Received 10 October 2007; Revised 27 December 2007; Accepted 11 February 2008; Published online 24 March 2008.
Abstract
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 Gi- and Gq-dependent pathways through activation of the Src (Gi) and protein kinase C (Gq) 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.
Keywords:
trophoblast, intracellular signal transmission, tumour cell growth, G-protein coupled receptor
Abbreviations:
EGF, epidermal growth factor; ET, endothelin; ETA, endothelin A; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; PTX, Pertussis toxin; RT-PCR, reverse transcription-PCR
