Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, No.2, Zheshan West Road, Wuhu, 241001, Anhui, China.
Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China.
Cell Biol Toxicol. 2024 Oct 30;40(1):93. doi: 10.1007/s10565-024-09931-z.
Cisplatin-based chemotherapy serves as the standard of care for individuals with advanced stages of gastric cancer. Nevertheless, the emergence of chemoresistance in GC has detrimental impacts on prognosis, yet the underlying mechanisms governing this phenomenon remain elusive. Level of mitophagy and ferroptosis of GC cells were detected by fluorescence, flow cytometry, GSH, MDA, Fe assays, and to explore the specific molecular mechanisms between NPR1 and cisplatin resistance by performing western blot and coimmunoprecipitation (co-IP) assays. These results indicates that NPR1 positively correlated with cisplatin-resistance and played a crucial part in conferring resistance to cisplatin in gastric cancer cells. Mechanistically, NPR1 affected levels of mitophagy and ferroptosis in human cisplatin-resistance GC cells with cisplatin treatment. Specifically, NPR1 inhibited mitophagy-dependent ferroptosis by reducing the ubiquitination-mediated degradation of PARL; moreover, NPR1 promoted PARL stabilization by disrupting the PARL-MARCH8 complex, which ultimately led to the development of chemoresistance in GC cells. Considering our findings, NPR1 appears to play an important role in chemotherapy for GC. NPR1 could potentially be used to overcome chemotherapy resistance.
顺铂为基础的化疗是晚期胃癌患者的标准治疗方法。然而，GC 中化疗耐药的出现对预后有不利影响，但控制这种现象的潜在机制仍不清楚。通过荧光、流式细胞术、GSH、MDA、Fe 测定法检测 GC 细胞的自噬和铁死亡水平，并通过 Western blot 和共免疫沉淀（co-IP）实验探索 NPR1 与顺铂耐药之间的具体分子机制。这些结果表明，NPR1 与顺铂耐药呈正相关，在胃癌细胞对顺铂耐药中发挥关键作用。在机制上，NPR1 通过减少 PARL 介导的泛素化降解来影响顺铂处理的人顺铂耐药 GC 细胞中的自噬依赖性铁死亡；此外，NPR1 通过破坏 PARL-MARCH8 复合物促进 PARL 稳定，最终导致 GC 细胞发生化疗耐药。鉴于我们的发现，NPR1 在 GC 的化疗中似乎起着重要作用。NPR1 可能被用于克服化疗耐药。
