AUTHOR=Xu Hao , Xing Jin , Cheng Lilin , Wang Zhihan , Zhao Liang , Ren Li , Zhang Shuai 

TITLE=CircFOXO3 upregulation mediates the radioresistance of glioblastoma by affecting cellular metabolome

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1479480

DOI=10.3389/fphar.2024.1479480

ISSN=1663-9812

ABSTRACT=Radioresistance remains a significant challenge in the treatment of glioblastoma multiforme (GBM), the most prevalent and lethal brain cancer in adults. Metabolic alterations are known to contribute to radioresistance through various mechanisms, including the activation of antioxidant responses to counteract reactive oxygen species and the promotion of DNA repair. In this study, we observed significant upregulation of circular RNA forkhead box O3 (circFOXO3) in glioma cells upon exposure to radiation and in recurrent GBM tissues. Knockdown of circFOXO3 was found to increase the radiosensitivity of glioma cells both in vitro and in vivo. Conversely, overexpression of circFOXO3 attenuated radiosensitivity in glioma cells. Metabolomic analysis revealed substantial alterations in the metabolomic profiles between the circFOXO3-overexpressing and control groups post-irradiation, particularly with respect to lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. Furthermore, the suppression of circFOXO3 expression increased the levels of the proapoptotic proteins Caspase 7 and Bax while decreasing Bcl-2 levels after radiotherapy. Our findings highlight the crucial role of circFOXO3 in promoting tumor radioresistance through metabolic modulation, underscoring its potential as a diagnostic and therapeutic target for GBM.