Gambogic Acid Induces Ferroptosis via miR-1291/FOXA2 Axis in Gastric Cancer.

Chun-Mei Qian, Liu Yang, Yi-Ying Wang, Zi-Liang Wang, Zi-Hang Xu, Mi-Die Xu, Xing Zhang, Xiao-Yu Wang
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Abstract

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, posing a significant threat to human health. Recently, gambogic acid (GA) has garnered attention for its anticancer properties in GC. However, it remains unclear whether GA can regulate other forms of cell death beyond apoptosis. In this study, we found that GA inhibited proliferation and induced ferroptosis in GC cells. Western blot analysis was employed to assess ferroptosis and endoplasmic reticulum (ER) stress-related proteins, as well as forkhead box A2 (FOXA2) expression. Additionally, malondialdehyde (MDA) and glutathione (GSH) levels were measured following GA treatment, and quantitative real-time polymerase chain reaction (RT-qPCR) was used to evaluate miR-1291 expression. Our findings revealed that GA treatment elevated reactive oxygen species (ROS) levels and promoted intracellular Fe[Formula: see text], MDA, and GSH accumulation. Furthermore, GA upregulated SLC7A11 and ferritin expression while suppressing glutathione peroxidase 4 (GPX4) in AGS and HGC27 cells, suggesting its role in ferroptosis induction. Notably, GA increased miR-1291 levels and downregulated FOXA2 expression. Subsequent analyses showed FOXA2 as a direct target of miR-1291. Functional experiments involving miR-1291 and FOXA2 knockdown or overexpression further suggested that the miR-1291/FOXA2 axis mediates ferroptosis. Finally, tumor xenograft models showed that GA effectively inhibited tumor growth by inducing ferroptosis. In conclusion, our study provides compelling evidence that GA induces ferroptosis in GC through the miR-1291/FOXA2 axis, highlighting its potential as a novel therapeutic strategy and preventive target for gastric cancer treatment.

藤黄酸通过miR-1291/FOXA2轴诱导胃癌铁下垂。
胃癌(GC)仍然是全球癌症相关死亡的主要原因,对人类健康构成重大威胁。近年来,藤黄酸(GA)因其在胃癌中的抗癌作用而受到广泛关注。然而,目前尚不清楚GA是否可以调节除细胞凋亡外的其他形式的细胞死亡。在本研究中,我们发现GA抑制GC细胞增殖并诱导铁下垂。Western blot检测铁下垂、内质网(ER)应激相关蛋白以及叉头盒A2 (FOXA2)表达。此外,测定GA处理后丙二醛(MDA)和谷胱甘肽(GSH)水平,并使用实时定量聚合酶链反应(RT-qPCR)评估miR-1291的表达。我们的研究结果表明,GA处理可提高活性氧(ROS)水平,促进细胞内铁(Fe)、MDA和GSH的积累。此外,GA在AGS和HGC27细胞中上调SLC7A11和铁蛋白的表达,同时抑制谷胱甘肽过氧化物酶4(谷胱甘肽过氧化物酶4),提示其在铁下垂诱导中的作用。值得注意的是,GA增加了miR-1291水平,下调了FOXA2的表达。随后的分析表明FOXA2是miR-1291的直接靶点。涉及miR-1291和FOXA2敲低或过表达的功能实验进一步表明,miR-1291/FOXA2轴介导铁下垂。最后,肿瘤异种移植模型显示,GA通过诱导铁下垂有效抑制肿瘤生长。总之,我们的研究提供了令人信服的证据,表明GA通过miR-1291/FOXA2轴诱导胃癌铁下垂,突出了其作为胃癌治疗的新治疗策略和预防靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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