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Updated: Jan 19, 2026
Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
Targeting Endothelin-1 Receptor/β-Arrestin-1 Axis in Ovarian Cancer: From Basic Research to a Therapeutic Approach
Piera Tocci1, Laura Rosanò1,2, Anna Bagnato1
1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy.
Abstract:
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.
Insights
Dual endothelin-1 receptor (ET-1R) antagonists, like macitentan, show promise in blocking cancer cell signaling. This approach may improve treatments by preventing drug resistance and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Endothelin-1 receptor (ET-1R), a G protein-coupled receptor (GPCR), is implicated in tumorigenesis and metastasis.
- The β-arrestin-1 (β-arr1) system is crucial for regulating GPCR signaling pathways.
- The ET-1R/β-arr1 axis in ovarian cancer presents a potential therapeutic target.
Purpose of the Study:
- To review emerging evidence on dual ET-1R antagonist treatment in cancer.
- To discuss the role of ET-1R/β-arr1 signaling in ovarian cancer progression.
- To highlight the potential for repurposing ET-1R antagonists in clinical settings.
Main Methods:
- Review of preclinical studies on ET-1R antagonists, specifically macitentan.
- Analysis of the impact of ET-1R blockade on β-arr1-mediated signaling.
- Examination of the effects on cancer cell communication and the tumor microenvironment.
Main Results:
- Macitentan, a dual ETAR/ETBR antagonist, counteracts β-arr1 signaling.
- ET-1R blockade interferes with cancer cell-microenvironment interactions, hindering metastasis.
- This blockade also impacts drug response and may overcome resistance mechanisms.
Conclusions:
- Dual ET-1R antagonists offer a promising strategy for cancer therapy.
- Repurposing ET-1R antagonists could lead to more effective clinical trials.
- Combinatorial therapies involving ET-1R antagonists may prevent or overcome drug resistance.
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