Beta-arrestin links endothelin A receptor to beta-catenin signaling to induce ovarian cancer cell invasion and metastasis

Laura Rosanò, Roberta Cianfrocca, Stefano Masi, Francesca Spinella, Valeriana Di Castro, Annamaria Biroccio, Erica Salvati, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato
Proceedings of the National Academy of Sciences of the United States of America 2009 February 24, 106 (8): 2806-11
The activation of endothelin-A receptor (ET(A)R) by endothelin-1 (ET-1) has a critical role in ovarian tumorigenesis and progression. To define the molecular mechanism in ET-1-induced tumor invasion and metastasis, we focused on beta-arrestins as scaffold and signaling proteins of G protein-coupled receptors. Here, we demonstrate that, in ovarian cancer cells, beta-arrestin is recruited to ET(A)R to form two trimeric complexes: one through the interaction with Src leading to epithelial growth factor receptor (EGFR) transactivation and beta-catenin Tyr phosphorylation, and the second through the physical association with axin, contributing to release and inactivation of glycogen synthase kinase (GSK)-3beta and beta-catenin stabilization. The engagement of beta-arrestin in these two signaling complexes concurs to activate beta-catenin signaling pathways. We then demonstrate that silencing of both beta-arrestin-1 and beta-arrestin-2 inhibits ET(A)R-driven signaling, causing suppression of Src, mitogen-activated protein kinase (MAPK), AKT activation, as well as EGFR transactivation and a complete inhibition of ET-1-induced beta-catenin/TCF transcriptional activity and cell invasion. ET(A)R blockade with the specific ET(A)R antagonist ZD4054 abrogates the engagement of beta-arrestin in the interplay between ET(A)R and the beta-catenin pathway in the invasive program. Finally, ET(A)R is expressed in 85% of human ovarian cancers and is preferentially co-expressed with beta-arrestin-1 in the advanced tumors. In a xenograft model of ovarian metastasis, HEY cancer cells expressing beta-arrestin-1 mutant metastasize at a reduced rate, highlighting the importance of this molecule in promoting metastases. ZD4054 treatment significantly inhibits metastases, suggesting that specific ET(A)R antagonists, by disabling multiple signaling activated by ET(A)R/beta-arrestin, may represent new therapeutic opportunities for ovarian cancer.

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