Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Rosanò, Laura; Cianfrocca, Roberta; Tocci, Piera; Spinella, Francesca; Castro, Valeriana Di; Caprara, Valentina; Semprucci, Elisa; Ferrandina, Gabriella; Natali, Pier Giorgio; Bagnato, Anna

doi:10.1158/0008-5472.can-13-3133

Cited by 89 publications

(117 citation statements)

References 45 publications

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“…In orthotopic OC models, it has been demonstrated direct involvements of ET-1 axis in promoting metastatic phenotype (13,(23)(24)(25)(26)28). Moreover, deeper studies showed that the metastatic phenotype is linked to the ET A R-␤-arr1-mediated pathways.…”

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

“…In particular, activation of the ET-1 pathway induces EMT through multiple distinct mechanisms, including the stabilization of the ␤-catenin protein, to engage transcription of genes related to EMT, through the ability of ␤-arr1 to serve as signal transducers in OC cells (23,25,26). Moreover, coexpression of ET A R and ␤-arr1 in human OC tissues is indicative of the malignant phenotype, and ET A R overexpression is associated with the switch of cadherin expression, indicating the relevant role of ET A R/␤-arr1 in the regulation of EMT and aggressive behavior (24,26).…”

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

“…Of note, treatment with macitentan prevented this signaling and restored drug sensitivity. Moreover, the combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, suggesting new combinatorial treatment with chemotherapy plus ET-1 therapeutics to improve sensitivity to chemotherapy (26). The strengths of the preclinical data driven by analysis of OC tissues from sensitive and resistant patients demonstrating that coexpression of ET A R and ␤-arr1, and the co-occupancy of ␤-arr1 and ␤-catenin on ET-1 gene promoter, appear to be indicative of the chemoresistant phenotype, further supporting the pathobiologic relevance of ET A R/␤-arr1 in the regulation of chemoresistance (26).…”

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

“…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%

“…In the majority of these cells, ET-1 acts by modulating cell survival pathways, and ET-1 receptor blockade with different receptor antagonists results in antitumor activity, by concomitant growth inhibition and apoptosis induction. At a therapeutic level, apoptotic responses of different tumor cells are potentiated when chemotherapeutic agents are combined with ET A R-selective antagonists (BQ123, atrasentan, and zibotentan) or dual ET A R and ET B R antagonists (macitentan), suggesting that combination of ET-1 therapeutics with chemotherapeutic drugs represents a viable option to stop compensatory pathways activated in response to therapeutics (17,24,26).…”

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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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Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells

et al. 2019

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Endothelin-1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin-1 rely on its activation by endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N-terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1c K6R ) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1c K6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self-renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2-dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC-like traits. Therefore, phospho-ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.

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