Titre
Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Lopez-Mejia, I.C.
Auteure/Auteur
Pijuan, J.
Auteure/Auteur
Navaridas, R.
Auteure/Auteur
Santacana, M.
Auteure/Auteur
Gatius, S.
Auteure/Auteur
Velasco, A.
Auteure/Auteur
Castellà, G.
Auteure/Auteur
Panosa, A.
Auteure/Auteur
Cabiscol, E.
Auteure/Auteur
Pinyol, M.
Auteure/Auteur
Coll, L.
Auteure/Auteur
Bonifaci, N.
Auteure/Auteur
Peña, L.P.
Auteure/Auteur
Vidal, A.
Auteure/Auteur
Villanueva, A.
Auteure/Auteur
Gari, E.
Auteure/Auteur
Llobet-Navàs, D.
Auteure/Auteur
Fajas, L.
Auteure/Auteur
Matias-Guiu, X.
Auteure/Auteur
Yeramian, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1878-0261
Statut éditorial
Publié
Date de publication
2023-01
Volume
17
Numéro
1
Première page
98
Dernière page/numéro d’article
118
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.
PID Serval
serval:BIB_549BE66DECEF
PMID
Open Access
Oui
Date de création
2022-11-28T13:44:59.383Z
Date de création dans IRIS
2025-05-20T16:29:50Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
36409196_BIB_549BE66DECEF.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
2.62 MB
Format
Adobe PDF
PID Serval
serval:BIB_549BE66DECEF.P001
URN
urn:nbn:ch:serval-BIB_549BE66DECEF5
Somme de contrôle
(MD5):6ba64205e79f5ace4fb6ed8d899a71a6