Journal
FRONTIERS IN ENDOCRINOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2019.00609
Keywords
endothelin-1; endothelin-1 receptors; ovarian cancer; beta-arrestin-1; G-protein coupled receptors
Categories
Funding
- Associazione Italiana Ricerca sul Cancro (AIRC) [AIRC IG18382, AIRC IG21372]
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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. beta-arrestin-1 (beta-arr1) system has been recognized as a critical hub controlling GPCR signaling network, directing the GPCR's biological outcomes. In ovarian cancer, ET-1 R/beta-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 beta-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.
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