细胞凋亡
GPX4
自噬
细胞生长
癌症研究
化学
癌细胞
程序性细胞死亡
体外
细胞
生物
癌症
生物化学
氧化应激
超氧化物歧化酶
谷胱甘肽过氧化物酶
遗传学
作者
Can Hu,Dan Zu,Jingli Xu,Hangdong Xu,Yuan Li,Jiahui Chen,Wei Qin,Yanqiang Zhang,Jing Han,Tao Lü,Junde Dong,Jiang‐Jiang Qin,Zhiyuan Xu,Xiuzhen Cheng
摘要
Gastric cancer (GC) is one of the most common malignant tumors in the world. GPx4, as the core regulator of ferroptosis, has become a potential molecular target for developing anticancer agents. In the present study, we found that GPx4 was overexpressed and negatively correlated with poor prognosis in GC, while it was associated with the GC development. Molecular docking and structure-based virtual screening assays were used to screen potential GPx4 inhibitors, and we identified a novel GPx4 inhibitor, polyphyllin B (PB), which can induce ferroptosis by down-regulating GPx4 expression in GC cells. It has also been shown to inhibit cell proliferation, suppress invasion and migration, induce apoptosis, and block the cell cycle progression in GC cells in vitro. Then, immunofluorescence and western blotting assay confirmed that PB can regulate the expression of LC3B, TFR1, NOCA4 and FTH1 in vitro, which suggested that suggest that PB may increase the level of Fe2+ by transporting Fe3+ into the cell by TFR1 and promoting NCOA4-dependent iron autophagy. In addition, PB can also suppresses tumor growth in an orthotopic mouse model of GC via regulating the expression of GPx4, TFR1, NOCA4 and FTH1 in vivo. In summary, we confirmed that GPx4 may be a potential target for GC treatment, PB may be a novel and promising drug for the treatment of GC, which shows good antitumor efficacy without causing significant host toxicity via inducing ferroptosis in both gastric cancer cells and mouse models.
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