Abstract
BackgroundCurrently, 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.MethodsExpression 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.ResultsTranscripts 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.ConclusionATF3 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.
Highlights
Resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy
Expression and prognosis of activating transcription factor 3 (ATF3) in gastric cancer cells and tissues To elucidate the function of ATF3 in Gastric cancer (GC), we first determined the expression of ATF3 in GC cells
Down‐regulation of ATF3 is validated in cisplatin‐resistant gastric cancer cells As presented in Fig. 2A, cisplatin-resistant GC cells (SGC7901/DDP and BGC823/ DDP) exhibited stronger resistance to cisplatin relative to the corresponding parental GC cells
Summary
Resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy. Gastric cancer (GC) currently ranks as the fifth most prevalent malignancy and the third in cancer-related mortality in modern society [1, 2]. GC poses a considerable health threat because epidemiological investigation confirms over 1 million estimated new cases of GC and almost 800,000 deaths annually [3]. Over 70% of GC cases occur in developing countries including China [4]. Traditional radical surgery and palliative chemotherapy remain the mainstay of GC treatment. Cisplatin (DDP)-based chemotherapy is deemed as a common first-line treatment for cancer patients including GC. GC patients with advanced disease usually acquire resistance to chemotherapy, resulting in a somber prognosis with a median overall survival of 8–11 months [5]
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