Endothelin-1 axis fosters YAP-induced chemotherapy escape in ovarian cancer.

Abstract

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.

• Authors: Piera Tocci, Roberta Cianfrocca, Rosanna Sestito, Laura Rosanò, Valeriana Di Castro, Giovanni Blandino, Anna Bagnato
• Journal: Cancer letters (Cancer Lett) Vol. 492 Pg. 84-95 (11 01 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32860850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• ARRB1 protein, human
• Cell Cycle Proteins
• Endothelin-1
• Receptor, Endothelin A
• Transcription Factors
• YY1AP1 protein, human
• beta-Arrestin 1
• Acyltransferases
• TAFAZZIN protein, human
• LATS1 protein, human
• Protein Serine-Threonine Kinases

Topics

• Acyltransferases
• Animals
• Apoptosis
• Cell Cycle Proteins (physiology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Endothelin-1 (physiology)
• Female
• Humans
• Mice
• Ovarian Neoplasms (drug therapy, pathology)
• Protein Serine-Threonine Kinases (physiology)
• Receptor, Endothelin A (physiology)
• Transcription Factors (physiology)
• beta-Arrestin 1 (physiology)