Endothelin-1 axis fosters YAP-induced chemotherapy escape in ovarian cancer
| Autor: | Anna Bagnato, Rosanna Sestito, Roberta Cianfrocca, Valeriana Di Castro, Piera Tocci, Giovanni Blandino, Laura Rosanò |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research RHOA medicine.drug_class Apoptosis Cell Cycle Proteins Protein Serine-Threonine Kinases 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Ovarian cancer Cell Line Tumor Medicine Animals Humans Receptor Macitentan Cisplatin Ovarian Neoplasms biology Endothelin-1 business.industry medicine.disease Receptor antagonist Receptor Endothelin A Endothelin 1 030104 developmental biology beta-Arrestin 1 Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Female business Acyltransferases medicine.drug Transcription Factors |
| Zdroj: | Cancer letters 492 (2020): 84–95. doi:10.1016/j.canlet.2020.08.026 info:cnr-pdr/source/autori:Tocci P.; Cianfrocca R.; Sestito R.; Rosano L.; Di Castro V.; Blandino G.; Bagnato A./titolo:Endothelin-1 axis fosters YAP-induced chemotherapy escape in ovarian cancer/doi:10.1016%2Fj.canlet.2020.08.026/rivista:Cancer letters (Print)/anno:2020/pagina_da:84/pagina_a:95/intervallo_pagine:84–95/volume:492 |
| ISSN: | 1872-7980 |
| DOI: | 10.1016/j.canlet.2020.08.026 |
| Popis: | The majority of ovarian cancer (OC) patients recur with a platinum-resistant disease. OC cells activate adaptive resistance mechanisms that are only partially described. Here we show that OC cells can adapt to chemotherapy through a positive-feedback loop that favors chemoresistance. In platinum-resistant OC cells we document that the endothelin-1 (ET-1)/endothelin A receptor axis intercepts the YAP pathway. This cross-talk occurs through the LATS/RhoA/actin-dependent pathway and contributes to prevent the chemotherapy-induced apoptosis. Mechanistically, β-arrestin1 (β-arr1) and YAP form a complex shaping TEAD-dependent transcriptional activity on the promoters of YAP target genes, including EDN1, which fuels a feed-forward signaling circuit that sustains a platinum-tolerant state. The FDA approved dual ET-1 receptor antagonist macitentan in co-therapy with cisplatin sensitizes resistant cells to the platinum-based therapy, reducing their metastatic potential. Furthermore, high ETAR/YAP gene expression signature is associated with a poor platinum-response in OC patients. Collectively, our findings identify in the networking between ET-1 and YAP pathways an escape strategy from chemotherapy. ET-1 receptor blockade interferes with such adaptive network and enhances platinum-induced apoptosis, representing a promising therapeutic opportunity to restore drug sensitivity in OC patients. |
| Databáze: | OpenAIRE |
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