The high mortality of @entity43 ( @entity43 ) is mainly caused by resistance to the available therapies. In @entity43 , the @entity2232 ( @entity2232 , @entity2232 )-endothelin A receptor ( @entity2231 , @entity2231 ) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how @entity2232 mediates drug resistance. Here, we define a novel bypass mechanism through which @entity2231 (b-arr1, @entity5262 ) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that @entity2231 /b-arr1 activity promoted nuclear complex with @entity3546 and @entity3493 , resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as @entity2232 , enhancing the network that sustains chemoresistance. Silencing of b-arr1 or pharmacologic treatment with the dual @entity2231 / @entity1627 antagonist @entity19629 prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo @entity19629 treatment reduced @entity5 growth, vascularization, intravasation, and metastatic progression. The combination of @entity19629 and @entity900 resulted in the potentiation of the cytotoxic effect, indicating that @entity19629 can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant @entity43 tissues confirmed increased recruitment of b-arr1 and @entity3546 to @entity2232 gene promoter. In these tissues, high expression of @entity2231 significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which @entity2231 /b-arr1 signaling is integrated with the Wnt/ @entity3546 pathway to sustain chemoresistance in @entity43 , and they offer a solid rationale for clinical evaluation of @entity19629 in combination with chemotherapy to overcome chemoresistance in this setting. @entity5 Res; 74(24); 7453-64.   2014 AACR.

Endothelin A Receptor/b-Arrestin Signaling to the Wnt Pathway Renders XXXX Cells Resistant to Chemotherapy.

@entity43 :: ('MESH:D010051', 'Disease') :: ['EOC', 'epithelial ovarian cancer'] @entity19629 :: ('MESH:C533860', 'Chemical') :: ['macitentan'] @entity2232 :: ('1906', 'Gene') :: ['endothelin-1', 'EDN1', 'ET-1'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'Cancer'] @entity900 :: ('MESH:D002945', 'Chemical') :: ['cisplatinum'] @entity5262 :: ('408', 'Gene') :: ['ARRB1'] @entity3493 :: ('2033', 'Gene') :: ['p300'] @entity1627 :: ('1910', 'Gene') :: ['ETBR'] @entity3546 :: ('1499', 'Gene') :: ['b-catenin'] @entity2231 :: ('1909', 'Gene') :: ['ETAR/b-arrestin-1', 'ETAR', 'EDNRA']
@entity43 :: (MESH:D010051,Disease) :: ['Ovarian Cancer']
