Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness

11Citations
Citations of this article
13Readers
Mendeley users who have this article in their library.

This article is free to access.

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.

References Powered by Scopus

Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012

23788Citations
N/AReaders
Get full text

Integrated genomic characterization of endometrial carcinoma

4071Citations
N/AReaders
Get full text

Oncogenic kinase signalling

3314Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Integrins in cancer: Emerging mechanisms and therapeutic opportunities

59Citations
N/AReaders
Get full text

Focal adhesion kinase: from biological functions to therapeutic strategies

38Citations
N/AReaders
Get full text

Roles and inhibitors of FAK in cancer: current advances and future directions

21Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Lopez-Mejia, I. C., Pijuan, J., Navaridas, R., Santacana, M., Gatius, S., Velasco, A., … Yeramian, A. (2023). Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness. Molecular Oncology, 17(1), 98–118. https://doi.org/10.1002/1878-0261.13346

Readers' Seniority

Tooltip

Researcher 3

60%

Professor / Associate Prof. 1

20%

PhD / Post grad / Masters / Doc 1

20%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 4

67%

Agricultural and Biological Sciences 1

17%

Business, Management and Accounting 1

17%

Save time finding and organizing research with Mendeley

Sign up for free