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
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.
引用
收藏
页码:2806 / 2811
页数:6
相关论文
共 32 条
[1]   Desensitization, internalization, and signaling functions of β-arrestins demonstrated by RNA interference [J].
Ahn, S ;
Nelson, CD ;
Garrison, TR ;
Miller, WE ;
Lefkowitz, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) :1740-1744
[2]   Emerging role of the endothelin axis in ovarian tumor progression [J].
Bagnato, A ;
Spinella, F ;
Rosanò, L .
ENDOCRINE-RELATED CANCER, 2005, 12 (04) :761-772
[3]   B-arrestins: Multifunctional cellular mediators [J].
Barki-Harrington, Liza ;
Rockman, Howard A. .
PHYSIOLOGY, 2008, 23 (01) :17-22
[4]   Regulation and intracellular trafficking pathways of the endothelin receptors [J].
Bremnes, T ;
Paasche, JD ;
Mehlum, A ;
Sandberg, C ;
Bremnes, B ;
Attramadal, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (23) :17596-17604
[5]   β-arrestin is a necessary component of Wnt/β-catenin signaling in vitro and in vivo [J].
Bryja, Vitezslav ;
Gradl, Dietmar ;
Schambony, Alexandra ;
Arenas, Ernest ;
Schulte, Gunnar .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (16) :6690-6695
[6]   Role of β-arrestin 1 in the metastatic progression of colorectal cancer [J].
Buchanan, FG ;
Gorden, DL ;
Matta, P ;
Shi, Q ;
Matrisian, LM ;
DuBois, RN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (05) :1492-1497
[7]   β-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins [J].
Chen, W ;
Hu, LYA ;
Semenov, MV ;
Yanagawa, S ;
Kikuchi, A ;
Lefkowitz, RJ ;
Miller, WE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :14889-14894
[8]   Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation [J].
Coluccia, Addolorata Maria Luce ;
Vacca, Angelo ;
Dunach, Mireia ;
Mologni, Luca ;
Redaelli, Sara ;
Bustos, Victor H. ;
Benati, Daniela ;
Pinna, Lorenzo A. ;
Gambacorti-Passerini, Carlo .
EMBO JOURNAL, 2007, 26 (05) :1456-1466
[9]   Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis:: Requirement for Akt activation [J].
Del Bufalo, D ;
Di Castro, V ;
Biroccio, A ;
Varmi, M ;
Salani, D ;
Rosanò, L ;
Trisciuoglio, D ;
Spinella, F ;
Bagnato, A .
MOLECULAR PHARMACOLOGY, 2002, 61 (03) :524-532
[10]   Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways [J].
Donninger, H ;
Bonome, T ;
Radonovich, M ;
Pise-Masison, CA ;
Brady, J ;
Shih, JH ;
Barrett, JC ;
Birrer, MJ .
ONCOGENE, 2004, 23 (49) :8065-8077