Fig. 1.

A: schematic model describing the potential mechanism by which β-arrestin-1 (β-arr1) regulates endothelin-1 (ET-1)-induced signaling pathways. In tumor cells ET-1 binding on receptors leads to recruitment of β-arr1. Then β-arr1 shuttles into the nucleus, where it interacts with a different transcriptional factor to form a complex with p300 required for histone acetylation and for the transcription of target genes, such as ET-1. This mechanism leads to the amplification of the ET-1 autocrine loop. As a signal transducer, β-arr1 initiates the transactivation of different receptor tyrosine kinase (RTK). In parallel, the autocrine/paracrine production of ET-1 activates ET_BR expressed on endothelial cells to promote angiogenesis and lymphangiogenesis and on microenvironmental cells. The dual ET_AR and ET_BR antagonist targets not only cancer cells (which express ET_AR and ET_BR) but also targets tumor-associated stromal elements, which express ET_BR, impairing growth, invasion, neovascularization, chemoresistance, and metastatic spread, and enhancing antitumor immune mechanisms. B: ET_AR overexpression is associated with improved survival of patients with ovarian cancer. Overall survival of 315 patients with high-grade serous ovarian cancer and ET_AR overexpression compared with normal expression (P < 0.01). Data were retrieved from TCGA data portal. C: β-arr1 is amplified in various human cancers. The cBio Cancer Genomics Portal (http://www.cbioportal.org/public-portal/) was queried for ARBB1 across various tumor datasets. The alteration frequency, type of alterations of β-arr1 gene (ARRB1), availability of mutation analysis, and Copy Number Alteration (CNA) in the various tumor cohorts are shown.