Conclusion
ACAT2 overexpression confers radioresistance by inhibiting ferroptosis in ESCC, suggesting ACAT2 could be a potential biomarker of poor radiotherapeutic response and a therapeutic target for enhancing the radiosensitivity of ESCC.
Purpose
The overall survival of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiation therapy (CCRT) resistance. The aim of this study is to use proteomics to identify a protein related to radiation therapy resistance and explore its molecular mechanisms.
Results
Enrichment analysis of differentially expressed proteins (<CR vs CR) showed that the pathways of molecules conferring CCRT resistance in ESCC were related to lipid metabolism, whereas molecules conferring CCRT sensitivity were mainly related to immunity pathways. ACAT2 was selected from proteomics and validated by immunohistochemistry as a risk factor for reduced overall survival and CCRT or radiation therapy resistance among ESCC patients. ACAT2 overexpression conferred resistance to IR treatment, whereas ACAT2 knockdown or knockout conferred IR sensitivity. ACAT2 knockout cells were prone to have elevated reactive oxygen species production, enhanced lipid peroxidation, and reduced levels of glutathione peroxidase 4 after IR compared with irradiated wild-type cells. ACAT2 knockout cells could be rescued from IR-mediated toxicity by ferrostatin-1 and liproxstatin.