共 32 条
β-Arrestin links endothelin A receptor to β-catenin signaling to induce ovarian cancer cell invasion and metastasis
被引:140
作者:
Rosano, Laura
[1
]
Cianfrocca, Roberta
[1
]
Masi, Stefano
[1
]
Spinella, Francesca
[1
]
Di Castro, Valeriana
[1
]
Biroccio, Annamaria
[2
]
Salvati, Erica
[2
]
Nicotra, Maria Rita
[4
]
Natali, Pier Giorgio
[1
,3
]
Bagnato, Anna
[1
]
机构:
[1] Regina Elena Inst Canc Res, Lab Mol Pathol, I-00158 Rome, Italy
[2] Regina Elena Inst Canc Res, Lab Expt Chemotherapy, I-00158 Rome, Italy
[3] Regina Elena Inst Canc Res, Immunol Lab, I-00158 Rome, Italy
[4] CNR, Mol Biol & Pathol Inst, I-00185 Rome, Italy
来源:
关键词:
beta-arrestin;
beta-catenin;
endothelin A receptor;
metastasis;
ovarian cancer;
GROWTH-FACTOR RECEPTOR;
CARCINOMA CELLS;
TYROSINE PHOSPHORYLATION;
TUMOR PROGRESSION;
EMERGING ROLE;
BETA-ARRESTIN1;
SRC;
TRANSACTIVATION;
ACTIVATION;
EXPRESSION;
D O I:
10.1073/pnas.0807158106
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
The activation of endothelin-A receptor (ETAR) 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 ETAR 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)-3 beta 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 ETAR-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. ETAR blockade with the specific ETAR antagonist ZD4054 abrogates the engagement of beta-arrestin in the interplay between ETAR and the beta-catenin pathway in the invasive program. Finally, ETAR 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 ETAR antagonists, by disabling multiple signaling activated by ETAR/beta-arrestin, may represent new therapeutic opportunities for ovarian cancer.
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页码:2806 / 2811
页数:6
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