Endothelin-1 and Prostaglandin-endoperoxide synthase 2 signaling axis (EDN1/PTGS2)

The EDN-1 and PTGS2 signaling nodes represent a critical regulatory axis where Endothelin-1 (EDN-1) induces the expression and activity of Prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) [1, 2]. This crosstalk is primarily mediated through the activation of Endothelin A receptors (ETAR), which triggers downstream signaling cascades such as MAPK and PI3K/Akt, leading to the transcriptional upregulation of PTGS2 [3, 5]. The resulting increase in prostaglandin E2 (PGE2) production promotes various pathological processes, including tumor cell proliferation, survival, angiogenesis, and epithelial-to-mesenchymal transition (EMT) [1, 4]. This axis is particularly prominent in several cancers, such as ovarian and prostate cancer, as well as in inflammatory and vascular diseases [3, 6]. Therapeutic strategies targeting this axis involve the use of endothelin receptor antagonists (ERAs) or selective COX-2 inhibitors to disrupt the feed-forward loop that drives disease progression [5, 7]. Research indicates that dual inhibition of these nodes may provide synergistic effects in reducing tumor growth and metastasis compared to single-agent therapy [3, 5]. Furthermore, this signaling axis plays a role in the development of chemoresistance, making it a significant focus for combination therapy development [7]. Clinical trials have explored the repurposing of ERAs in combination with other agents to target this pathway in oncology [7].

Other names

ET-1/COX-2 axisEndothelin-1/Cyclooxygenase-2 signaling pathwayEDN1-PTGS2 signaling nodesEndothelin-1 and COX-2 signaling axisEDN1-PTGS2 axis

The signaling axis is targeted by inhibiting the upstream ligand (Endothelin-1) or its receptors (ETAR/ETBR) using endothelin receptor antagonists, or by inhibiting the downstream enzyme (PTGS2/COX-2) using selective or non-selective inhibitors [1, 3]. This disruption prevents the induction of pro-tumorigenic and pro-inflammatory mediators like PGE2 and VEGF [5].