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.

hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process / Di Modugno, Francesca; Caprara, Valentina; Chellini, Lidia; Tocci, Piera; Spadaro, Francesca; Ferrandina, Gabriella; Sacconi, Andrea; Blandino, Giovanni; Nisticò, Paola; Bagnato, Anna; Rosanò, Laura. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - (2018), p. 201715998. [10.1073/pnas.1715998115]

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

Tocci, Piera;
2018

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.
2018
endothelin receptor; hMENA; invadopodia; ovarian cancer; β-arrestin
01 Pubblicazione su rivista::01a Articolo in rivista
hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process / Di Modugno, Francesca; Caprara, Valentina; Chellini, Lidia; Tocci, Piera; Spadaro, Francesca; Ferrandina, Gabriella; Sacconi, Andrea; Blandino, Giovanni; Nisticò, Paola; Bagnato, Anna; Rosanò, Laura. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - (2018), p. 201715998. [10.1073/pnas.1715998115]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1070774
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