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

Abstract

SignificanceDiscovering new targets and novel determinants of metastatic spread is an unmet need in ovarian cancer, which is plagued by high rates of recurrence. Endothelin-1 receptors (ET-1R), belonging to the G-protein–coupled receptor family, represent important targets critically involved in malignant progression. Here we identify a mechanistic link between ET-1R and the actin regulatory protein hMENA/hMENAΔv6 through the specific interaction with the multifunctional protein β-arrestin1 (β-arr1), which initiates signaling cascades as part of the molecular complex crucial for invadopodial maturation and malignant dissemination. Targeting ET-1R by using macitentan, a Food and Drug Administration-approved antipulmonary arterial hypertension drug, can impair the β-arr1–mediated signaling network controlling ovarian cancer progression and therefore represents a therapeutic option for ovarian cancer patients.

hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis

“…In pancreatic cancer cells, expression of hMENAΔv6, along with a lack of hMENA 11a , is crucial for SMAD2-mediated-TGFβ signaling and invasiveness [ 11 ]. In ovarian cancer, we have recently described an essential function of hMENA/hMENAΔv6 for endothelin1/β-arrestin1-induced invadopodial activity and cancer progression [ 15 ].…”

β-Arrestin1 mediates hMENA expression and ovarian cancer metastasis

“…Hence, β-arrestins regulate specific cellular functions as a result of interacting with defined partner proteins. In PNAS, Di Modugno et al (9) identify hMENA, an actin binding protein of the ENA/VASP family, as a novel interacting partner of β-arr1 critical for endothelin-1 (ET-1) and its cognate receptor ET 1A R signaling in ovarian cancer cell invasion and metastasis ( Fig. 1).…”

“…Nonetheless, only minimal improvement in the mortality has been observed over the past decade, pointing to the molecular complexity of ovarian cancer and resultant obstacles in developing effective therapies (11). Di Modugno et al (9) used complementary strategies of gene overexpression and knockdown, together with pharmacologic activators and inhibitors, to credibly implicate ET 1A R, β-arr1, and hMENA as mediators of HGSC invasion and metastasis. To implicate ET 1A R, the authors used macitentan, a dual ET 1A R/ET 1B R ligand antagonist, and showed that treatment with macitentan obliterated the ET-1-induced expression of hMENA and proinvasive isoform hMENAΔv6, but decreased expression of the antiinvasive hMENA 11a isoform.…”

“…The nuclear expression of β-arr1 implies a potential role in transcription regulation, and previous work has shown that nuclear β-arr1 interacts with transcription regulators, including p300 (15), E2F (16), β-catenin (8), and HIF-1α (17) to regulate expression of their target genes. In PNAS, Di Modugno et al (9) report that stimulation with ET-1 promotes ENAH gene expression in a manner that is dependent upon expression of β-arr1, but not β-arr2. Moreover, the authors show that the ET-1/ET 1A R/β-arr1 axis differentially regulates expression of hMENA isoforms: stimulation of ovarian cancer cells with ET-1 increases expression of the wild-type and proinvasive hMENAΔv6 isoform but decreases expression of antiinvasive hMENA 11a .…”

“…Furthermore, activated β2AR induced the β-arr1-mediated expression of the tumor-suppressor RASGRF2, with consequent effect on Rac and cofilin activities, actin remodeling, and cell migration (21). Di Modugno et al (9) report that ET-1 promotes relocalization of β-arr1/hMENA/PDZ-RhoGEF from the periphery in the tips of actin stress fiber-like structures to the cytosol to colocalize with F-actin/cortactin-enriched microdomains, leading to the activation of RhoC and invadopodia maturation. Hence, engaged β-arr1 forms complex with a particular RhoGEF to activate a Rho GTPase that is required for actin cytoskeleton rearrangement and cell invasion.…”