Silencing ribosome biogenesis regulator 1 homolog (RRS1) inhibits angiogenesis and cisplatin resistance of lung cancer cells by activating ferroptosis mediated by p53 pathway

BACKGROUND: Human RRS1 gene is abnormally expressed in many cancers, and RRS1 can inhibit the level of p53. Ferroptosis mediated by p53 pathway may be a potential therapeutic strategy for cancer. However, the specific role of RRS1 in lung cancer is not clear. METHODS: The correlation between the expression level of RRS1 and the overall survival of lung cancer patients was explored through UALCAN and Kaplan-Meier plotter. A549 cells and drug-resistant A549/DDP cells were used in vitro. Wound healing, Transwell and tubule formation experiment were used to detect the abilities of cell invasion, migration and tube formation. Detecting the level of lipid ROS by BODIPY(581/591) C11 staining, the expression level of total iron and ferroptosis-related proteins were detected, so as to judge the ferroptosis in cells. Detecting the apoptosis by flow cytometry and the expression of apoptosis-related proteins by western blot, so as to observe the effect of interfering with RRS1 on cisplatin resistance of cells. RESULTS: The expression of RRS1 was up-regulated, and its level was negatively correlated with the overall survival time of lung cancer patients. In vitro experiments showed that RRS1 interference reduced the invasion and migration of lung cancer cells, inhibited the expressions of MMP2 and MMP9 proteins and decreased the tube-forming ability of cells. After interfering with RRS1, the level of p53, lipid ROS and the total iron content in cells increased, the expression of SLC7A11 and GPX4 decreased while the expression of ACSL4 increased, which indicated that ferroptosis was enhanced. Interference with RRS1 increased the apoptosis of drug-resistant cells, decreased the expression of Bcl2 while increased the expression of Bax and caspase3(cleaved), which decreased the cisplatin resistance of lung cancer cell A549. However, after silencing p53, these effects were reversed. CONCLUSION: RRS1 inhibits angiogenesis and cisplatin resistance of lung cancer cells by activating ferroptosis mediated by p53 pathway.