Endothelin A receptor drives invadopodia function and cell motility through the β-arrestin/PDZ-RhoGEF pathway in ovarian carcinoma
| Autor: | Anna Bagnato, Roberta Cianfrocca, Francesca Spadaro, Piera Tocci, Valentina Caprara, M Veglione, V Di Castro, Gabriella Ferrandina, Elisa Semprucci, Rosanna Sestito, Laura Rosanò |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
rho GTP-Binding Proteins RHOA RhoC Cell Movement Rho GTpase molecular biology genetics invasion beta-Arrestins invadopodia Ovarian Neoplasms rho-Associated Kinases biology Reverse Transcriptase Polymerase Chain Reaction Lim Kinases cytoskeleton Cofilin Receptor Endothelin A Hedgehog signaling pathway Cell biology Actin Depolymerizing Factors rhoC GTP-Binding Protein Invadopodia Podosomes Female RNA Interference Cortactin RhoC GTP-Binding Protein Signal Transduction cancer research Immunoblotting Transplantation Heterologous Mice Nude Actin Depolymerizing Factors / metabolism 03 medical and health sciences Cell Line Tumor Matrix Metalloproteinase 14 Animals Humans cancer Kinase activity Actins Adaptor Proteins Vesicular Transport 030104 developmental biology Settore MED/40 - GINECOLOGIA E OSTETRICIA biology.protein Rho Guanine Nucleotide Exchange Factors |
| Zdroj: | Oncogene (Basingstoke) 35 (2016): 3432–3442. doi:10.1038/onc.2015.403 info:cnr-pdr/source/autori:Semprucci, E.; Tocci, P.; Cianfrocca, R.; Sestito, R.; Caprara, V.; Veglione, M.; Di Castro, V.; Spadaro, F.; Ferrandina, G.; Bagnato, A.; Rosano, L./titolo:Endothelin A receptor drives invadopodia function and cell motility through the beta-arrestin%2FPDZ-RhoGEF pathway in ovarian carcinoma/doi:10.1038%2Fonc.2015.403/rivista:Oncogene (Basingstoke)/anno:2016/pagina_da:3432/pagina_a:3442/intervallo_pagine:3432–3442/volume:35 |
| DOI: | 10.1038/onc.2015.403 |
| Popis: | The endothelin-1 (ET-1)/ET A receptor (ETAR) signalling pathway is a well-established driver of epithelial ovarian cancer (EOC) progression. One key process promoted by ET-1 is tumor cell invasion, which requires the scaffolding functions of beta-arrestin-1 (beta-arr1) downstream of the receptor; however, the potential role of ET-1 in inducing invadopodia, which are crucial for cellular invasion and tumor metastasis, is completely unknown. We describe here that ET-1/ETAR, through beta-arr1, activates RhoA and RhoC GTPase and downstream ROCK (Rho-associated coiled coil-forming kinase) kinase activity, promoting actin-based dynamic remodelling and enhanced cell invasion. This is accomplished by the direct interaction of beta-arr1 with PDZ-RhoGEF (postsynaptic density protein 95/disc-large/zonula occludens-RhoGEF). Interestingly, ETAR-mediated invasive properties are related to the regulation of invadopodia, as evaluated by colocalization of actin with cortactin, as well as with TKS5 and MT1-MMP (membrane type 1-matrix metalloproteinase) with areas of matrix degradation, and activation of cofilin pathway, which is crucial for regulating invadopodia activity. Depletion of PDZ-RhoGEF, or beta-arr1, or RhoC, as well as the treatment with the dual ET-1 receptor antagonist macitentan, significantly impairs invadopodia function, MMP activity and invasion, demonstrating that beta-arr1/PDZ-RhoGEF interaction mediates ETAR-driven ROCK-LIMK-cofilin pathway through the control of RhoC activity. In vivo, macitentan is able to inhibit metastatic dissemination and cofilin phosphorylation. Collectively, our data unveil a noncanonical activation of the RhoC/ROCK pathway through the beta-arr1/PDZ-RhoGEF complex as a regulator of ETAR-induced motility and metastasis, establishing ET-1 axis as a novel regulator of invadopodia protrusions through the RhoC/ROCK/LIMK/cofilin pathway during the initial steps of EOC invasion. |
| Databáze: | OpenAIRE |
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