Abstract
The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.
Highlights
G protein-coupled receptors (GPCR) play key roles in different cellular processes
The ability of Yes-associated protein (YAP)/transcriptional coactivator with PDZbinding motif (TAZ) to directly control the transcription of Endothelin receptors (ET-1R) ligand, contributes to understand how the β-arr1-mediated signals control the complex spatio-temporal regulation of tumor cell plasticity
How ET-1R/β-arr1 and YAP/TAZ signaling are integrated within different contexts is still not well-defined, we can envision that this interplay occurs between distinct cell types, as stromal and epithelial cells embedded in the extracellular matrix (ECM), adding complexity to the emerging model (Fig. 1)
Summary
G protein-coupled receptors (GPCR) play key roles in different cellular processes. As such, aberrant activation of GPCR can alter the signaling landscape and cellular fate in multiple pathophysiologic contexts including cancer. Beside the β-arr and 2 canonical roles in directing GPCR desensitization, internalization and G-protein signaling termination, increasing evidence highlights an alternative signaling machinery in which β-arr isoforms act as signal transducers that convert their established proteinprotein interaction into signaling pattern independent from G-protein activities Both β-arr isoforms guide a complex signaling exchange that leads to unique cellular responses providing a selective advantage to tumor cells [15, 17, 19–35]. The diverse β-arr localization profiles affect their interaction pattern, that for β-arr includes many transcription factors, co-factors and epigenetic regulators [26–35] In this landscape, growing evidence discloses how β-arr connects the ETAR signaling with other pathways fostering ETARintertwined signalings critically involved in the metastatic progression and drug response in many tumor types, including ovarian cancer [20–38]. Such analysis may hold the exciting potential to unveil new vulnerabilities facilitating the design of generation therapies able to dismantle the ET-1R/YAP-generated oncogenic network
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