Endothelin A receptor/β-arrestin signaling to the Wnt pathway renders ovarian cancer cells resistant to chemotherapy.
The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ETAR, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ETAR/β-arrestin-1 (β-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ETAR/β-arr1 activity promoted nuclear complex with β-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of β-arr1 or pharmacologic treatment with the dual ETAR/ETBR antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of β-arr1 and β-catenin to ET-1 gene promoter. In these tissues, high expression of ETAR significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ETAR/β-arr1 signaling is integrated with the Wnt/β-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting.
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy. bagnato@ifo.it rosano@ifo.it.
Laura
L
Rosanò
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Roberta
R
Cianfrocca
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Piera
P
Tocci
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Francesca
F
Spinella
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Valeriana
V
Di Castro
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Valentina
V
Caprara
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Elisa
E
Semprucci
Gynecologic Oncology Unit, Catholic University of Rome, Italy.
Gabriella
G
Ferrandina
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy. Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO) Laboratories, University Gabriele d'Annunzio, Chieti, Italy.
Pier Giorgio
PG
Natali
Molecular Pathology Laboratory, Regina Elena National Cancer Institute, Rome, Italy. bagnato@ifo.it rosano@ifo.it.
Anna
A
Bagnato
D019390:Arrestins / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019332:Endothelin-1 / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D044022:Receptor, Endothelin A / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D019390:Arrestins; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins