title: β-arrestin1 at the cross-road of endothelin-1 signaling in cancer.
abstract: The advent of targeted therapeutics in human cancer has begun to find novel druggable targets and, in this context, the endothelin-1 receptor (ET-1R), namely ETA receptor (ETAR) and ETB receptor, among the GPCR family represents a class of highly druggable molecules in cancer. ET-1R are aberrantly expressed in human malignancies, potentially representing prognostic factors. Their activation by ligand stimulation initiate signaling cascades activating different downstream effectors, allowing precise control over multiple signaling pathways. ET-1R regulates cell proliferation, survival, motility, cytoskeletal changes, angiogenesis, metastasis as well as drug resistance. The molecular events underlying these responses are the activation of transcriptional factors and coactivators, and downstream genes, acting as key players in tumor growth and progression. ET-1R represent crucial cancer targets that have been exploited for ET-1R therapeutics. Importantly, efforts to explore new information of ETAR in cancer have uncovered that their functions are crucially regulated by multifunctional scaffold protein β-arrestins (β-arrs) which orchestrate the multidimensionality of ETAR signaling into highly regulated and distinct signaling complexes, a property that is highly advantageous for tumor signaling. Moreover, the role of β-arr1 in ET-1 signaling in cancer highlights why the pleiotropic effects of ET-1 and its dynamic signaling are more complex than previously recognized. In order to improve therapeutic strategies that interfere with the widespread effects of ET-1R, it is important to consider antagonists able to turn the receptors "off" selectively controlling β-arr1-dependent signaling, highlighting the possibility that targeting ETAR/β-arr1 may display a large therapeutic window in cancer.
authors.affiliation: Preclinical Models and New Therapeutic Agents Unit, Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144, Rome, Italy. laura.rosano@ifo.gov.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.affiliation: Preclinical Models and New Therapeutic Agents Unit, Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144, Rome, Italy. annateresa.bagnato@ifo.gov.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D019332:Endothelin-1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D015398:Signal Transduction; D000071559:beta-Arrestin 1 / Q000378:metabolism*
chemical_list: C000605253:ARRB1 protein, human; C000588596:EDNRB protein, human; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000071559:beta-Arrestin 1
keywords: Cancer; Endothelin; Endothelin receptors; G-protein coupled receptors; β-arrestin