Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling

Abstract

BACKGROUND: Currently, resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy. Here, we sought to investigate the function of activating transcription factor 3 (ATF3) n GC chemoresistance. METHODS: Expression of ATF3 was determined in GC cell lines (MNK45, SGC7901, and BGC823) and cisplatin (DDP)-resistant cells (SGC7901/DDP and BGC823/DDP). Biological informatics was performed to analyze ATF3 expression and prognosis in GC patients. Cisplatin resistance was evaluated. Ferroptosis was detected after ATF3 transfection of cells. The underlying molecular mechanism was also investigated. RESULTS: Transcripts of ATF3 were decreased in GC cells and GC tissues. Kaplan-Meier plotter analysis revealed that ATF3 expression was positively related to the overall survival of GC patients. In particular, lower levels of ATF3 were observed in cisplatin-resistant SGC7901/DDP and BGC823/DDP relative to their parental cells. Notably, ATF3 elevation sensitized cisplatin-resistant cells to cisplatin. Mechanically, compared with parental cells, SGC7901/DDP and BGC823/DDP cells exhibited lower ferroptosis evident by lower ROS, MDA and lipid peroxidation and higher intracellular GSH levels. However, ATF3 elevated ferroptosis in SGC7901/DDP and BGC823/DDP cells. Intriguingly, ATF3 overexpression together with ferroptosis activator erastin or RSL3 treatment further enhanced ferroptosis and cisplatin resistance; however, the ferroptosis suppressor liproxstatin-1 reversed the function of ATF3 in ferroptosis and cisplatin resistance. Additionally, cisplatin-resistant cells exhibited stronger activation of Nrf2/Keap1/xCT signaling relative to parental cells, which was restrained by ATF3 up-regulation. Importantly, restoring Nrf2 signaling overturned ATF3-mediated ferroptosis and cisplatin resistance. CONCLUSION: ATF3 may sensitize GC cells to cisplatin by induction of ferroptosis via blocking Nrf2/Keap1/xCT signaling, supporting a promising therapeutic approach for overcoming chemoresistance in GC.