Beta-arrestin links endothelin A receptor to beta-catenin signaling to induce ovarian cancer cell invasion and metastasis.
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.
Rosanò
Laura
L
Laboratories of Molecular Pathology, Experimental Chemotherapy, and Immunology, Regina Elena Cancer Institute, 00158 Rome, Italy.
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
D019390:Arrestins / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; D019390:Arrestins; D044022:Receptor, Endothelin A; D051176:beta Catenin; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D014443:Tyrosine; D066246:ErbB Receptors