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. 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. 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. 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.

中文翻译：

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ATF3升高诱导铁死亡通过抑制Nrf2/Keap1/xCT信号减轻胃癌顺铂耐药

目前，对顺铂 (DDP) 的耐药性是晚期胃癌 (GC) 化疗成功的常见问题。在这里，我们试图研究激活转录因子 3 (ATF3) n GC 化学抗性的功能。在 GC 细胞系（MNK45、SGC7901 和 BGC823）和顺铂 (DDP) 抗性细胞（SGC7901/DDP 和 BGC823/DDP）中测定了 ATF3 的表达。进行生物信息学分析 GC 患者的 ATF3 表达和预后。评估顺铂抗性。在ATF3转染细胞后检测到铁死亡。还研究了潜在的分子机制。ATF3 的转录在 GC 细胞和 GC 组织中减少。Kaplan-Meier 绘图仪分析显示 ATF3 表达与 GC 患者的总生存期呈正相关。特别是，在顺铂抗性 SGC7901/DDP 和 BGC823/DDP 中观察到的 ATF3 水平低于其亲代细胞。值得注意的是，ATF3 升高使顺铂耐药细胞对顺铂敏感。在机械上，与亲本细胞相比，SGC7901/DDP 和 BGC823/DDP 细胞表现出较低的铁死亡，这明显是由于较低的 ROS、MDA 和脂质过氧化以及较高的细胞内 GSH 水平。然而，ATF3 提高了 SGC7901/DDP 和 BGC823/DDP 细胞中的铁死亡。有趣的是，ATF3 过表达与铁死亡激活剂erastin 或RSL3 处理一起进一步增强了铁死亡和顺铂抗性；然而，铁死亡抑制因子 liproxstatin-1 逆转了 ATF3 在铁死亡和顺铂耐药中的功能。此外，与亲本细胞相比，顺铂抗性细胞表现出更强的 Nrf2/Keap1/xCT 信号激活，这受到 ATF3 上调的抑制。重要的是，恢复 Nrf2 信号会推翻 ATF3 介导的铁死亡和顺铂耐药。ATF3 可能通过阻断 Nrf2/Keap1/xCT 信号传导诱导铁死亡，从而使 GC 细胞对顺铂敏感，支持一种有希望的治疗方法来克服 GC 的化学抗性。