Endocrine Abstracts

Previous studies have demonstrated over-expression of cyclooxygenase-2 (COX-2) enzyme and enhanced synthesis of prostanoids, such as prostaglandin E₂ (PGE₂), in cervical carcinomas. PGE₂ mediates its is effects by interacting with one of four receptors termed EP1-4. Expression and signalling of EP receptors, including EP4, are elevated in cervical carcinomas. We have previously proposed that in addition to endogenous PGE₂, EP receptors in cervical carcinomas can be activated by seminal plasma prostaglandins. Prostaglandin concentration in seminal plasma is 10,000 times higher than that found at a site of inflammation, and PGE₂ is the predominant type of prostaglandin detected in semen. In this study we investigated the potential activation of the EP4 receptor by seminal plasma prostaglandins in wild type (WT) and EP4 receptor over-expressing (EP4S) cervical adenocarcinoma (HeLa) cells. Treatment of EP4S cells with seminal plasma results in a rapid accumulation of cAMP (P<0.001) and phosphorylation of ERK1/2 (P<0.001) compared with WT cells. The phosphorylation of ERK1/2 is inhibited by co-treatment of cells with seminal plasma and MEK inhibitor (PD98059), EP4-selective receptor antagonist (ONO-AE2-227) or an inhibitor of epidermal growth factor (EGF) receptor tyrosine kinase (AG1478). Treatment of EP4S cells with seminal plasma also resulted in elevated expression of COX-2 (P<0.001) and vascular endothelial growth factor (VEGF; P<0.001). Expression of these genes is inhibited by co-treatment of cells with seminal plasma and the MEK inhibitor, the EP4-selective receptor antagonist or the EGF receptor tyrosine kinase inhibitor. In conclusion, our data demonstrate that seminal plasma prostaglandins can activate signalling and expression of inflammatory and angiogenic genes via EP4 receptors, which may involve transactivation of the EGF receptor and ERK1/2 in the downstream signalling cascade. This suggests that cervical carcinoma in sexually active women may be exacerbated following exposure to seminal plasma and activation of EP-receptor signal transduction pathways.