Endothelin-1 induces the transactivation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells

Spinella, Francesca; Caprara, Valentina; Castro, Valeriana Di; Rosanò, Laura; Cianfrocca, Roberta; Natali, Pier Giorgio; Bagnato, Anna

doi:10.1007/s00109-012-0956-2

Cited by 49 publications

(43 citation statements)

References 34 publications

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“…These comparisons showed similarly high levels of expression for the above genes. Of note, the GPCRs GRM1 and EDNRB, which can activate the AKT pathway (27,28), were overexpressed in PV2.…”

Section: A Resistant Subcutaneous Metastasis Pv1 Harbors Two Nras Mmentioning

confidence: 98%

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression

Romano

Pradervand

Paillusson

et al. 2013

Clinical Cancer Research

115

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Purpose: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we conducted a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAF V600E -mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug. Experimental Design: We obtained blood and tissue samples from a patient diagnosed with a BRAF V600E -mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully rechallenged with vemurafenib. Exome and RNA sequencing were conducted on a pretreatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1) and one that occurred de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed.Results: We identified two NRAS-activating somatic mutations, Q61R and Q61K, affecting two main subpopulations in the metastasis PV1 and a BRAF alternative splicing, involving exons 4-10, in the metastasis PV2. These alterations, known to confer resistance to RAF inhibitors, were tumor-specific, mutually exclusive, and were not detected in pretreatment tumor samples. In addition, the oncogenic PIK3CA H1047R mutation was detected in a subpopulation of PV1, but this mutation did not seem to play a major role in vemurafenib resistance in this metastasis.Conclusions: This work describes the coexistence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma.

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“…These comparisons showed similarly high levels of expression for the above genes. Of note, the GPCRs GRM1 and EDNRB, which can activate the AKT pathway (27,28), were overexpressed in PV2.…”

Section: A Resistant Subcutaneous Metastasis Pv1 Harbors Two Nras Mmentioning

confidence: 98%

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression

Romano

Pradervand

Paillusson

et al. 2013

Clinical Cancer Research

115

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“…Hence, ET A R and ET B R, which are heterogeneously expressed in EOC cells (14,15), have emerged as key targets for cancer therapy. A complex cross-talk between ET-1 signaling and other growth factor pathways drives tumor progression via the scaffold protein b-arrestin (b-arr, ARRB1) that serves as molecular hub to organize complex signaling network (16)(17)(18)(19). Some noteworthy cross-talk is the ET-1-mediated transactivation of receptor tyrosine kinases and b-catenin signaling (17,19).…”

Section: Introductionmentioning

confidence: 99%

“…A complex cross-talk between ET-1 signaling and other growth factor pathways drives tumor progression via the scaffold protein b-arrestin (b-arr, ARRB1) that serves as molecular hub to organize complex signaling network (16)(17)(18)(19). Some noteworthy cross-talk is the ET-1-mediated transactivation of receptor tyrosine kinases and b-catenin signaling (17,19). The canonical Wnt pathway results in b-catenin nuclear accumulation and transcriptional activation of target genes.…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant accumulation of b-catenin correlates with EOC tumor grade and poor survival (20,21) and deregulation of Wnt/b-catenin signaling is a key factor in inducing and maintaining chemoresistance in EOC (22,23). Although recent evidence suggests that downstream of ET A R, b-arr1 serves as component of functional complexes for b-catenin stabilization, and invasive behavior (18,19), a complete picture of the underlying molecular mechanisms leading to chemoresistance remains to be elucidated. In this study, we reveal a signaling framework relevant for chemoresistance, providing evidence for a novel integration between ET A R/b-arr1 signaling and the b-catenin pathway, leading to chemoresistance onset.…”

Section: Introductionmentioning

confidence: 99%

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

Rosanò¹,

Cianfrocca²,

Tocci³

et al. 2014

Cancer Research

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107

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The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ET A R, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ET A R/b-arrestin-1 (b-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ET A R/b-arr1 activity promoted nuclear complex with b-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of b-arr1 or pharmacologic treatment with the dual ET A R/ET B R antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of b-arr1 and b-catenin to ET-1 gene promoter. In these tissues, high expression of ET A R significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ET A R/b-arr1 signaling is integrated with the Wnt/b-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting. Cancer Res; 74(24); 7453-64. Ó2014 AACR.

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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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Endothelin-1 induces the transactivation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells

Cited by 49 publications

References 34 publications

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression

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

Endothelin therapeutics in cancer: Where are we?

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