Targeting Endothelin-1 Receptor/β-Arrestin-1 Axis in Ovarian Cancer: From Basic Research to a Therapeutic Approach

• Main Authors: Piera Tocci, Laura Rosanò, Anna Bagnato
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-09-01
• Series: Frontiers in Endocrinology
• Subjects: endothelin-1; endothelin-1 receptors; ovarian cancer; β-arrestin-1; G-protein coupled receptors
• Online Access: https://www.frontiersin.org/article/10.3389/fendo.2019.00609/full

Recent studies imply a key role of endothelin-1 receptor (ET-1R), belonging to the largest family of G protein-coupled receptors (GPCR), in the regulation of a plethora of processes involved in tumorigenesis and metastatic progression. β-arrestin-1 (β-arr1) system has been recognized as a critical hub controlling GPCR signaling network, directing the GPCR's biological outcomes. In ovarian cancer, ET-1R/β-arr1 axis enables cancer cells to engage several integrated signaling, and represents an actionable target for developing novel therapeutic approaches. Preclinical research studies demonstrate that ET-1R blockade by the approved dual ETAR/ETBR antagonist macitentan counteracts β-arr1-mediated signaling network, and hampers the dialogue among cancer cells and the tumor microenvironment, interfering with metastatic progression and drug response. In light of major developments in the ET-1R signaling paradigm, this review article discusses the emerging evidence of the dual ET-1R antagonist treatment in cancer, and outlines our challenge in preclinical studies warranting the repurposing of ET-1R antagonists for the design of more effective clinical trials based on combinatorial therapies to overcome, or prevent, the onset of drug resistance.