氧化锌纳米颗粒通过介导自噬依赖性铁死亡来减轻卵巢癌的恶性进展。
Zinc oxide nanoparticles mitigate the malignant progression of ovarian cancer by mediating autophagy-dependent ferroptosis.
机构信息
Department of Gynecology, The General Hospital of Ningxia Medical University, 804 Shengli South Street, Xingqing District, Yinchuan, Ningxia, 750001, China.
出版信息
J Cancer Res Clin Oncol. 2024 Nov 27;150(12):513. doi: 10.1007/s00432-024-06029-1.
BACKGROUND
Previous studies have shown that ZnO-NPs induce autophagy and inhibit the malignant progression of ovarian cancer (OC) cells. This study aims to further explore the mechanism of action of ZnO-NPs on OC.
METHODS
SKOV3 cells were treat with different concentrations of ZnO-NPs and cell proliferation was assessed through EDU staining. A Xenograft tumor model was established and mice were treated with varying doses of ZnO-NPs for 21 days. Tumor volume and the weight of each group of mice were measured, and the expression of KI67 in tumor tissues was analyzed to evaluate tumor proliferation in vivo. The expression of autophagy and ferroptosis-related proteins in cells and tumor tissues was examined through immunofluorescence, ELISA, and western blotting assays. The relationship between ZnO-NPs induced autophagy and ferroptosis was further investigated using the ferroptosis inhibitors Fer-1, autophagy inhibitor 3-MA and siRNA for ATG5 (si-ATG5).
RESULTS
ZnO-NPs dose-dependently reduced the proliferation of SKOV3 cells in vitro. In vivo, both high and low doses of ZnO-NPs effectively inhibited the growth of tumor, reduced pathological damage and the expression of KI67 in tumor tissues. Additionally, ZnO-NPs increased the levels of iron, MDA, 4-HNE, oxidized lipid ROS, ATG5, TFR1, ACSL4, LC3, and Beclin1 in cells and tumor tissues, decreased the expression of SOD, GSH-Px, non-oxidized lipid ROS, GPX4, and p62. Transfection with si-ATG5 or treatment with 3-MA significantly weakened these effects of ZnO-NPs in vitro, with si-ATG5 having a stronger weakening effect on the action of ZnO-NPs than 3-MA. However, ferroptosis inhibitor has a lesser impact on the autophagy of ZnO-NPs-treated SKOV3 cells than the effect of autophagy inhibitors and si-ATG5 on the ferroptosis of ZnO-NPs-treated SKOV3 cells.
CONCLUSION
ZnO-NPs inhibited the malignant progression of SKOV3 cells by inducing autophagy-dependent ferroptosis.
背景
先前的研究表明，氧化锌纳米粒子（ZnO-NPs）可诱导自噬并抑制卵巢癌细胞（OC）的恶性进展。本研究旨在进一步探讨 ZnO-NPs 对 OC 的作用机制。
方法
用不同浓度的 ZnO-NPs 处理 SKOV3 细胞，通过 EDU 染色评估细胞增殖。建立异种移植肿瘤模型，用不同剂量的 ZnO-NPs 处理小鼠 21 天。测量各组小鼠的肿瘤体积和重量，并分析肿瘤组织中 KI67 的表达，以评估体内肿瘤增殖。通过免疫荧光、ELISA 和 Western blot 检测细胞和肿瘤组织中自噬和铁死亡相关蛋白的表达。用铁死亡抑制剂 Fer-1、自噬抑制剂 3-MA 和 ATG5（si-ATG5）siRNA 进一步研究 ZnO-NPs 诱导的自噬与铁死亡之间的关系。
结果
ZnO-NPs 呈剂量依赖性降低 SKOV3 细胞在体外的增殖。体内，高、低剂量的 ZnO-NPs 均能有效抑制肿瘤生长，减轻肿瘤组织的病理损伤和 KI67 的表达。此外，ZnO-NPs 增加了细胞和肿瘤组织中铁、MDA、4-HNE、氧化脂质 ROS、ATG5、TFR1、ACSL4、LC3 和 Beclin1 的水平，降低了 SOD、GSH-Px、非氧化脂质 ROS、GPX4 和 p62 的表达。体外转染 si-ATG5 或用 3-MA 处理显著减弱了 ZnO-NPs 的这些作用，si-ATG5 对 ZnO-NPs 作用的减弱作用强于 3-MA。然而，铁死亡抑制剂对 ZnO-NPs 处理的 SKOV3 细胞自噬的影响小于自噬抑制剂和 si-ATG5 对 ZnO-NPs 处理的 SKOV3 细胞铁死亡的影响。
结论
ZnO-NPs 通过诱导自噬依赖性铁死亡抑制 SKOV3 细胞的恶性进展。
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