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

Autor: Tocci P; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy., Cianfrocca R; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy., Sestito R; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy., Rosanò L; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy; Institute of Molecular Biology and Pathology, CNR, Rome, Italy., Di Castro V; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy., Blandino G; Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy., Bagnato A; Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy. Electronic address: annateresa.bagnato@ifo.gov.it.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2020 Nov 01; Vol. 492, pp. 84-95. Date of Electronic Publication: 2020 Aug 26.
DOI: 10.1016/j.canlet.2020.08.026
Abstrakt: 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 ET A R/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.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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