Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis

Teoh, Jian Peng; Wang, Yongchao; Hu, Qian-Nan; Kim, Sangmi; Wu, Guangyu; Huang, Shuang; Maihle, Nita J.; Kim, Il-man

doi:10.1016/j.cellsig.2014.08.024

Cited by 25 publications

(22 citation statements)

References 64 publications

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“…Specific cases can be made for biased antagonism as well for future work. For example, Biased Receptor Signaling the natural agonist endothelin 1 activates endothelin A receptors to cause oncogenic (Ga q -coupled and/or b-arrestin signaling; Spinella et al, 2004;Rosanò et al, 2013;Teoh et al, 2014) and tumor-suppressive (Ga s -signaling; Takahashi et al, 2009;Follin-Arbelet et al, 2013;Teoh et al, 2014) effects. On balance, patients with ovarian cancer and high levels of endothelin A receptors were shown to have a low survival rate (Follin-Arbelet et al, 2013), yet endothelin receptor antagonists appeared to be ineffective as a cancer treatment (Cognetti et al, 2013).…”

Section: Biased Antagonismmentioning

confidence: 99%

Biased Receptor Signaling in Drug Discovery

2019

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Section: Biased Antagonismmentioning

confidence: 99%

Biased Receptor Signaling in Drug Discovery

2019

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“…The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig.…”

mentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ␤-arrestin 1 (␤-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ET AR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ␤-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.␤-arrestin; cancer; endothelin-1; endothelin-1 receptor; target therapy RECENT INVESTIGATIONS have consistently suggested that endothelin-1 (ET-1), a small bioactive peptide of 21 residues derived from longer prepro-ET-1 precursor, is an important signal messenger in different pathological conditions, including human cancers (24,35). ET-1 belongs to a family of closely related peptides that include ET-2 and ET-3, which are all similar in structure to ET-1, but are separate gene products, with tissue-specific expression. ETs act mainly via G protein-coupled receptors (GPCR) from endothelin receptor type A (ET A R) and B (ET B R) (24). The two receptors can be differentiated by agonists and antagonists binding affinity and in their cellular distributions. The ET A R binds ET-1 with the greatest affinity, whereas ET-1, ET-2, and ET-3 all have equal affinity for the ET B R.It is now well known that ET-1 receptors can activate several signaling pathways in a G protein-independent manner via complexes with ␤-arrestin (␤-arr)-1 or -2 (18, 24). The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig. 1A). A lesson learned from various tumor models is that there are different expression profiles of the ET-1 receptors compared with normal tissues. There are cancers expres...

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“…The known oncogenic downstream effects of ET A R are mediated by Gα q -coupled or β-arrestin-dependent signaling pathways (Spinella et al ., 2004; Rosano et al ., 2013a). It was shown that GRK5/6-mediated phosphorylation of the receptor leads to the recruitment and nuclear translocation of β-arrestin, which in turn functions as an epigenetic regulator of several angiogenic/metastatic genes including β-catenin, thus promoting cell invasion (Rosano et al ., 2013a; Teoh et al ., 2014). On the other hand, ET A R-mediated Gα s activation induces AC/cAMP/PKA signaling, which can confer tumor suppressive effects as reported in several carcinoma-derived cell lines (Takahashi et al ., 2009; Follin-Arbelet et al ., 2013; Teoh et al ., 2014).…”

Section: Biased Signaling On Selected Gpcrsmentioning

confidence: 99%

“…It was shown that GRK5/6-mediated phosphorylation of the receptor leads to the recruitment and nuclear translocation of β-arrestin, which in turn functions as an epigenetic regulator of several angiogenic/metastatic genes including β-catenin, thus promoting cell invasion (Rosano et al ., 2013a; Teoh et al ., 2014). On the other hand, ET A R-mediated Gα s activation induces AC/cAMP/PKA signaling, which can confer tumor suppressive effects as reported in several carcinoma-derived cell lines (Takahashi et al ., 2009; Follin-Arbelet et al ., 2013; Teoh et al ., 2014). Given that stimulation of the ET-1/ET A R axis can activate both tumor suppressive and oncogenic properties in cancer cells, ligands biased toward Gα s /cAMP/PKA signaling might represent a novel potential therapy of various malignancies.…”

Section: Biased Signaling On Selected Gpcrsmentioning

confidence: 99%

“…In ovarian cancer, ET A R/ET-1 axis has been shown to promote tumorigenesis by promoting anti-apoptosis, invasion, and neoangiogenesis (Spinella et al ., 2004; Rosano et al ., 2005). Indeed, ET A R overexpression is associated with poor survival in patients with ovarian carcinoma (Teoh et al ., 2014). However, a recent clinical study demonstrated that specific ET A R antagonists are ineffective as auxiliary anti-cancer treatment (Cognetti et al ., 2013).…”

Section: Biased Signaling On Selected Gpcrsmentioning

confidence: 99%

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Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

Bologna

Teoh

Bayoumi

et al. 2017

Biomolecules & Therapeutics

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G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

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Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis

Cited by 25 publications

References 64 publications

Biased Receptor Signaling in Drug Discovery

Biased Receptor Signaling in Drug Discovery

Endothelin therapeutics in cancer: Where are we?

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

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