YAP and endothelin-1 signaling: an emerging alliance in cancer

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.

High Endothelin Receptor Type A Expression as an Independent Prognostic Biomarker and Correlated with Immune Infiltrates in Stomach Adenocarcinoma

“… 7 , 8 In addition, the EDNRA/ET-1 axis participates in the reprogramming of tumor-associated immune cells, such as neutrophils, 9 dendritic cells (DC), 10 tumor-associated macrophages (TAM), 11 , 12 tumor infiltrating lymphocytes (TIL) 13 and regulates the communication between tumor cells and tumor microenvironment (TME). 14 The existing body of research on bladder cancer suggests EDNRA is one of immune function-related genes, and has the potential to assess prognosis and predict the efficacy of immunotherapy. 15 Wei et al observed that EDNRA expression can be downregulated by miR-200c in regulation of gastric carcinoma cells proliferation, apoptosis and invasiveness.…”

YAP1 Overexpression Is Associated with Kidney Dysfunction in Lupus Nephritis

“…YAP is not only a transcriptional coactivator of many target genes in the nucleus but also a key effector of the Hippo signaling pathway. As YAP can regulate cell proliferation, differentiation, and apoptosis, it can control the size of organs and prevent tumorigenesis [46]. After the Hippo pathway is activated by various extracellular signals, YAP is phosphorylated at serine/threonine residues, inactivated by cytoplasmic isolation, and finally degraded by the proteasome [45].…”

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine

“…ET-1/ET-1R axis activation gives cells the potential to exert changes in cell fate and accomplish deleterious features [ 296 ]. ET-1 expression has been detected in numerous malignancies such as in advanced tumoral contexts [ 297 , 298 ], where elevated ET-1R indicated worsened prognosis [ 296 ].…”

“…ET-1/ET-1R axis activation gives cells the potential to exert changes in cell fate and accomplish deleterious features [ 296 ]. ET-1 expression has been detected in numerous malignancies such as in advanced tumoral contexts [ 297 , 298 ], where elevated ET-1R indicated worsened prognosis [ 296 ]. Within tumours, ET-1 generates signals which induce pro-survival transcriptional answers, securing tumoral cells from cancer therapy-induced apoptosis [ 297 , 299 , 300 ].…”