Abstract
The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antineoplastic Agents
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Cell Line, Tumor
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Cell Survival / drug effects
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Cystadenocarcinoma, Serous / drug therapy
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Cystadenocarcinoma, Serous / genetics
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Cystadenocarcinoma, Serous / metabolism*
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Disease Models, Animal
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Endothelin-1 / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Guanine Nucleotide Exchange Factors / metabolism
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Humans
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Mice, Nude
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Mutation
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / pharmacology
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Receptor, Endothelin A / drug effects
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Receptor, Endothelin A / metabolism*
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Signal Transduction*
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Sulfonamides / pharmacology
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
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beta-Arrestin 1 / drug effects
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beta-Arrestin 1 / metabolism*
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rho GTP-Binding Proteins / metabolism
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rhoA GTP-Binding Protein / metabolism
Substances
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ARRB1 protein, human
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Endothelin-1
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Guanine Nucleotide Exchange Factors
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Pyrimidines
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Receptor, Endothelin A
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RhoH protein, human
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Sulfonamides
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Transcription Factors
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Tumor Suppressor Protein p53
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YAP-Signaling Proteins
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YAP1 protein, human
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beta-Arrestin 1
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Protein Serine-Threonine Kinases
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TRIO protein, human
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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macitentan