Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.
Details
Serval ID
serval:BIB_549BE66DECEF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.
Journal
Molecular oncology
ISSN
1878-0261 (Electronic)
ISSN-L
1574-7891
Publication state
Published
Issued date
01/2023
Peer-reviewed
Oui
Volume
17
Number
1
Pages
98-118
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
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.
Keywords
Humans, Antioxidants/metabolism, Cell Line, Tumor, Cell Movement, Cystadenocarcinoma, Serous/drug therapy, Cystadenocarcinoma, Serous/pathology, Focal Adhesion Kinase 1/metabolism, Oxidative Stress, Phosphorylation, Reactive Oxygen Species, Tyrosine/metabolism, Animals, focal adhesion kinase, migration, reactive oxygen species, uterine serous carcinoma
Pubmed
Web of science
Open Access
Yes
Create date
28/11/2022 15:44
Last modification date
23/01/2024 8:25