Titre
Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma.
Type
article
Institution
Externe
Périodique
Auteur(s)
Xu, D.
Auteure/Auteur
Yang, H.
Auteure/Auteur
Yang, Z.
Auteure/Auteur
Berezowska, S.
Auteure/Auteur
Gao, Y.
Auteure/Auteur
Liang, S.Q.
Auteure/Auteur
Marti, T.M.
Auteure/Auteur
Hall, SRR
Auteure/Auteur
Dorn, P.
Auteure/Auteur
Kocher, G.J.
Auteure/Auteur
Schmid, R.A.
Auteure/Auteur
Peng, R.W.
Auteure/Auteur
Liens vers les personnes
ISSN
2072-6694
Statut éditorial
Publié
Date de publication
2019-10-08
Volume
11
Numéro
10
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.
PID Serval
serval:BIB_28A911170DC1
PMID
Open Access
Oui
Date de création
2020-06-29T07:38:16.851Z
Date de création dans IRIS
2025-05-20T20:12:49Z