TY - JOUR
T1 - HMENA is a key regulator in endothelin-1/β-arrestin1- induced invadopodial function and metastatic process
AU - Di Modugno, Francesca
AU - Caprara, Valentina
AU - Chellini, Lidia
AU - Tocci, Piera
AU - Spadaro, Francesca
AU - Ferrandina, Maria Gabriella
AU - Sacconi, Andrea
AU - Blandino, Giovanni
AU - Nisticò, Paola
AU - Bagnato, Anna
AU - Rosanò, Laura
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Endothelin receptor
KW - HMENA
KW - Invadopodia
KW - Multidisciplinary
KW - Ovarian cancer
KW - β-arrestin
KW - Endothelin receptor
KW - HMENA
KW - Invadopodia
KW - Multidisciplinary
KW - Ovarian cancer
KW - β-arrestin
UR - http://hdl.handle.net/10807/122318
UR - http://www.pnas.org/content/pnas/115/12/3132.full.pdf
U2 - 10.1073/pnas.1715998115
DO - 10.1073/pnas.1715998115
M3 - Article
SN - 0027-8424
VL - 115
SP - 3132
EP - 3137
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
ER -