Zhao Yue, Wang Yixiao, Zhang Xinyi, Han Shuqi, Yang Bo
Department of Oncology and Gynecology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui Province, China.
Department of Oncology and Gynecology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui Province, China.
Reprod Biol. 2025 Mar;25(1):100968. doi: 10.1016/j.repbio.2024.100968. Epub 2024 Dec 16.
Metformin (Met), a widely used type II diabetes medication, has shown anti-cancer properties in various cancers. RBMS3 is a tumor suppressor implicated in several cancers, including ovarian cancer. Ferroptosis, a novel form of programmed cell death, is gaining attention in cancer research. This study explores whether metformin induces ferroptosis and inhibits ovarian cancer progression through the RBMS3 pathway. We used a CCK-8 assay to determine the optimal metformin concentration for ovarian cancer cells. Metformin's effects were further evaluated using EdU assay and flow cytometry. To clarify its mechanism, we employed programmed cell death inhibitors and measured levels of MDA (Malondialdehyde), GSH (Glutathione), and Fe²⁺. Ferroptosis-related proteins and RBMS3 expression in ovarian cancer tissues and cells were assessed via RT-qPCR and Western blotting. A xenograft mouse model was used to observe metformin's effects on tumor growth. Metformin inhibited the viability of ovarian cancer A2780 cells, promoted ferroptosis, increased MDA and Fe²⁺ levels, and reduced GSH. It upregulated ferroptosis-related genes while downregulating GPX4 and SLC7A11. Although RBMS3 was reduced in cancer cells, metformin increased its expression, and silencing RBMS3 reversed metformin's effects. In vivo, metformin inhibited tumor growth, which was negated by RBMS3 silencing. Our findings suggest that metformin promotes ferroptosis and inhibits ovarian cancer progression by upregulating RBMS3, offering a promising direction for clinical application in ovarian cancer treatment.
二甲双胍（Met）是一种广泛使用的II型糖尿病药物，已在多种癌症中显示出抗癌特性。RBMS3是一种肿瘤抑制因子，与包括卵巢癌在内的多种癌症有关。铁死亡是一种新型的程序性细胞死亡形式，在癌症研究中越来越受到关注。本研究探讨二甲双胍是否通过RBMS3途径诱导铁死亡并抑制卵巢癌进展。我们使用CCK-8试验来确定卵巢癌细胞的最佳二甲双胍浓度。使用EdU试验和流式细胞术进一步评估二甲双胍的作用。为了阐明其机制，我们使用了程序性细胞死亡抑制剂，并测量了丙二醛（MDA）、谷胱甘肽（GSH）和Fe²⁺的水平。通过RT-qPCR和蛋白质印迹法评估卵巢癌组织和细胞中铁死亡相关蛋白和RBMS3的表达。使用异种移植小鼠模型观察二甲双胍对肿瘤生长的影响。二甲双胍抑制卵巢癌A2780细胞的活力，促进铁死亡，增加MDA和Fe²⁺水平，并降低GSH。它上调铁死亡相关基因，同时下调GPX4和SLC7A11。尽管癌细胞中RBMS3减少，但二甲双胍增加了其表达，沉默RBMS3可逆转二甲双胍的作用。在体内，二甲双胍抑制肿瘤生长，而RBMS3沉默可消除这种作用。我们的研究结果表明，二甲双胍通过上调RBMS3促进铁死亡并抑制卵巢癌进展，为卵巢癌治疗的临床应用提供了一个有前景的方向。
