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.
Highlights
The endothelin (ET) family comprises three isoforms of small peptides, ET-1, ET-2 and ET-3, products of different genes [1]
ETs activate two receptor subtypes that belong to the G protein-coupled receptors (GPCR), known as ETA receptor (ETAR) and ETB receptor (ETBR), displaying 63 % similarity [1, 2]
We first outline how ET-1/endothelin-1 receptor (ET-1R) axis underlies many features of cancers; in the second part, we review a large body of works on the specific role of β-arrs in different tumors; in the third part, we detailed the various β-arr-dependent signalings upon ET-1R activation in cancer
Summary
The endothelin (ET) family comprises three isoforms of small peptides, ET-1, ET-2 and ET-3, products of different genes [1]. Role of β-arrestin in cancer Emerging data have revealed that β-arr recruitment represents a major non-G protein-dependent signaling pathway of GPCR, like ET-1R, in cancer This function is largely related to the ability of β-arr to act as multifunctional adaptor capable to finely modulate multiple signaling pathways involved in tumor growth and metastasis, driven mainly by GPCRs (Table 1), and by other non-GPCR pathways, such as transforming growth factor (TGF)-β, Hedgehog, Wingless, and Notch. One the best characterized signaling pathways mediated by β-arr is linked to non-receptor tyrosine kinase c-Src. in different human cancer, such as prostate, colorectal, breast or gastric cancer, a complex and functional interaction between β-arr and c-Src driven by activation of GPCR, like prostanoid receptor 4, chemokine receptor-7 or GPR39, mediates the cross-talk with other several signaling, such as EGFR or Wnt signaling, representing additional mechanisms by which GPCR can sustain long-term biological responses [31,32,33,34]. This regulation can occur either by scaffolding signaling proteins, such as Arp2/3 complex and WASP family of proteins or Rap, RhoA and Ral GTPases, or by directly binding
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