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Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):3132-3137. doi: 10.1073/pnas.1715998115. Epub 2018 Feb 8.

hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process.

Author information

1
Unit of Tumor Immunology and Immunotherapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, 00144 Rome, Italy.
2
Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, 00144 Rome, Italy.
3
Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
4
Gynecologic Oncology Unit, Catholic University of Rome, 00168 Rome, Italy.
5
Unit of Oncogenomic and Epigenetic, IRCCS, Regina Elena National Cancer Institute, 00144 Rome, Italy.
6
Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, 00144 Rome, Italy; annateresa.bagnato@ifo.gov.it laura.rosano@ifo.gov.it.

Abstract

Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAΔv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAΔv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/β-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENAΔv6 for ET-1/β-arr1-induced invadopodial activity and ovarian cancer progression.

KEYWORDS:

endothelin receptor; hMENA; invadopodia; ovarian cancer; β-arrestin

PMID:
29439204
PMCID:
PMC5866561
DOI:
10.1073/pnas.1715998115
[Indexed for MEDLINE]
Free PMC Article

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