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

Piera Tocci, Roberta Cianfrocca, Rosanna Sestito, Laura Rosanò, Valeriana Di Castro, Giovanni Blandino, Anna Bagnato

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)84-95
Number of pages12
JournalCancer Letters
Volume492
DOIs
Publication statusPublished - Nov 1 2020

Keywords

  • Chemoresistance
  • Endothelin-1 receptor
  • Ovarian cancer
  • YAP
  • β-arrestin1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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