Titre
MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Yang, H.
Auteure/Auteur
Gao, Y.
Auteure/Auteur
Xu, D.
Auteure/Auteur
Xu, K.
Auteure/Auteur
Liang, S.Q.
Auteure/Auteur
Yang, Z.
Auteure/Auteur
Scherz, A.
Auteure/Auteur
Hall, SRR
Auteure/Auteur
Forster, S.
Auteure/Auteur
Berezowska, S.
Auteure/Auteur
Yao, F.
Auteure/Auteur
Ochsenbein, A.F.
Auteure/Auteur
Marti, T.M.
Auteure/Auteur
Kocher, G.J.
Auteure/Auteur
Schmid, R.A.
Auteure/Auteur
Dorn, P.
Auteure/Auteur
Peng, R.W.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2058-7716
Statut éditorial
Publié
Date de publication
2023-02-10
Volume
9
Numéro
1
Première page
55
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.
PID Serval
serval:BIB_09EB04B0CBA2
PMID
Open Access
Oui
Date de création
2023-02-13T06:49:36.442Z
Date de création dans IRIS
2025-05-20T16:10:38Z
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Nom
s41420-023-01307-2.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
10.26 MB
Format
Adobe PDF
PID Serval
serval:BIB_09EB04B0CBA2.P001
URN
urn:nbn:ch:serval-BIB_09EB04B0CBA23
Somme de contrôle
(MD5):f61e41abfd72edefe84ddf27f99b6456