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

ABSTRACT: 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.

SUBMITTER: Rosano L

PROVIDER: S-EPMC2650347 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Rosanò Laura L Cianfrocca Roberta R Masi Stefano S Spinella Francesca F Di Castro Valeriana V Biroccio Annamaria A Salvati Erica E Nicotra Maria Rita MR Natali Pier Giorgio PG Bagnato Anna A

Proceedings of the National Academy of Sciences of the United States of America 20090206 8

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 fa ...[more]

PMID: 19202075

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Dataset Information

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

Publications

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

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