The FBXO32/ATR/ATM axis acts as a molecular switch to control the sensitivity of osteosarcoma cells to irradiation through its regulation of EXO1 expression.
Acta Biochim Biophys Sin (Shanghai)
; 55(5): 842-852, 2023 May 24.
Article
em En
| MEDLINE
| ID: mdl-37227155
ABSTRACT
Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. In clinical treatments, the insensitivity of OS to conventional radiotherapy regimens significantly contributes to poor patient prognosis and survival. EXO1 is responsible for DNA repair pathways and telomere maintenance. Meanwhile, ATM and ATR are considered switches because they can regulate the expression of EXO1. However, their expression and interaction in OS cells under irradiation (IR) remain unclear. This study aims to investigate the roles of FBXO32, ATM, ATR and EXO1 in OS radiotherapy insensitivity and poor patient prognosis and explore potential pathogenic mechanisms. Bioinformatics is employed to analyse differential gene expression and correlations with prognosis in OS. Cell counting kit 8 assay, clone formation assay, and flow cytometry are used to evaluate cell survival and apopotosis under IR. Co-IP assay is used to detect proteinâprotein interactions. Bioinformatics analysis reveals that EXO1 is closely related to survival, apoptosis and poor prognosis in OS. Silencing of EXO1 suppresses cell proliferation and increases the sensitivity of OS cells. Molecular biological experiments show that ATM and ATR act as switches to regulate EXO1 expression under IR. Higher expression of EXO1, which is closely correlated with IR insensitivity and poorer prognosis, might be used as a prognostic indicator for OS. Phosphorylated ATM enhances the expression of EXO1, and phosphorylated ATR induces the degradation of EXO1. More importantly, FBXO32 degrades ATR via ubiquitination in a time-dependent manner. Our data may provide a reference for future research in the mechanisms, clinical diagnosis, and treatment of OS.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias Ósseas
/
Osteossarcoma
Tipo de estudo:
Diagnostic_studies
Limite:
Adolescent
/
Child
/
Humans
Idioma:
En
Revista:
Acta Biochim Biophys Sin (Shanghai)
Assunto da revista:
BIOFISICA
/
BIOQUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China