Shandong Cancer Hospital Affiliated to Shandong First Medical University Jinan, Shandong
Y. Xu1, H. Yu1, D. Chen2, J. Yu2, and W. Wen3; 1Shandong Cancer Hospital and Institute, Jinan, Shandong, China, 2Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 3Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shangdong, China
Purpose/Objective(s): To investigate the impact of lipid metabolism abnormalities on the radioresistance of Non-Small Cell Lung Cancer (NSCLC) and explore the mechanism of targeting cholesterol synthesis pathway to sensitize NSCLC to radiotherapy. Materials/
Methods: Cells were irradiated with X-Ray. Cholesterol synthesis-related gene expression of cells was detected by real-time quantitative PCR (RT-PCR). Oil Red O staining was performed to detect the intracellular lipid accumulation. Colony formation assay was used to determine the ability of cell clone formation. Survival fractions were fitted with single-hit multi-target model to estimate sensitizer enhancement ratio (SER). Neutral comet assay was performed for detecting DNA double-strand breaks (DSBs). Western blot analysis was adopted for the evaluation of the expression of DNA damage-related proteins and ferroptosis-related proteins. Lipid peroxidation was estimated using the C11-BODIPY 581/591 fluorescent probe. Results: Radiation enhanced cholesterol synthesis in NSCLC, which increased lipid deposition and promote NSCLC resistance to radiotherapy. The cholesterol-lowering statins could aggravate the DSBs and inhibit DNA damage repair protein ATM expression to increase the sensitivity of radiotherapy. In addition, radiation-induced lipid metabolism disorders caused GPX4, a negative regulator of ferroptosis, high expression in NSCLC. Statins could decrease GPX4 expression by downregulating ATM expression, leading to increased ferroptosis and heightened radiosensitivity. This effect may be due to the influence of statins on the mevalonate pathway. Conclusion: Radiation-induced elevation of cholesterol metabolism in NSCLC was related to radiotherapy resistance. Statins could impede DNA damage repair and increase ferroptosis levels in NSCLC by targeting the mevalonate pathway, thus enhanced the radiosensitivity of NSCLC.
