Guoqiang Qin, Xin Luo, Ge Zou, Qishan Mo, Weide Zhong
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引用次数: 0
Abstract
Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to current therapies. A tumor microenvironment-responsive nanoplatform was developed to couple chemodynamic therapy with modulation of oncogenic lipid metabolism.
Methods: A graphene oxide-doped copper-based metal-organic framework (GO-CuMOF) was prepared by ultrasonicating solvothermally synthesized CuMOF with graphene oxide, and was characterized physicochemically. Its generation of hydroxyl radicals (•OH) was confirmed by a methylene blue degradation assay. Antitumor activity was evaluated in DU145 and PC3 cells and in a PC3 xenograft model. Untargeted metabolomic and proteomic profiling was integrated with data from The Cancer Genome Atlas prostate adenocarcinoma cohort, and the candidate targets were validated by enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative PCR, and Western blotting.
Results: In the presence of glutathione (GSH), GO-CuMOF released Cu⁺, depleting GSH and generating •OH. It raised intracellular reactive oxygen species (ROS), induced apoptosis, and suppressed CRPC cell proliferation and xenograft growth without reducing body weight or causing overt organ toxicity. Multi-omics profiling showed CYP2J2 downregulation, with accumulation of its substrate linoleate and reduction of 9(10)- and 12(13)-epoxyoctadecenoic acid (EpOME), the latter confirmed by ELISA. CYP2J2 was the most consistently associated candidate across proteomic and public-cohort evidence.
Conclusion: GO-CuMOF exerts concurrent chemodynamic ROS generation and CYP2J2-associated changes in linoleic acid metabolism. The CYP2J2-EpOME axis represents a candidate metabolism-directed vulnerability for CRPC that warrants functional and clinical validation.
目的：去势抵抗性前列腺癌（CRPC）对目前的治疗反应较差。研究人员开发了一个肿瘤微环境响应纳米平台，将化学动力学治疗与致癌脂质代谢调节结合起来。方法：采用超声溶剂热法制备氧化石墨烯掺杂铜基金属有机骨架（GO-CuMOF），并对其进行物理化学表征。通过亚甲基蓝降解实验证实了其羟基自由基（•OH）的生成。在DU145和PC3细胞以及PC3异种移植模型中评估抗肿瘤活性。非靶向代谢组学和蛋白质组学分析与癌症基因组图谱（The Cancer Genome Atlas前列腺癌队列）的数据相结合，并通过酶联免疫吸附试验（ELISA）、反转录定量PCR和Western blotting验证候选靶点。结果：在谷胱甘肽（GSH）存在下，GO-CuMOF释放出Cu⁺，消耗GSH，生成•OH。它增加细胞内活性氧（ROS），诱导细胞凋亡，抑制CRPC细胞增殖和异种移植物生长，而不会减轻体重或引起明显的器官毒性。多组学分析显示CYP2J2下调，其底物亚油酸积累，9(10)-和12(13)-环氧十八烯酸（EpOME）减少，后者通过ELISA证实。CYP2J2是蛋白质组学和公共队列证据中最一致的相关候选者。结论：GO-CuMOF在亚油酸代谢中同时产生ROS和cyp2j2相关的化学动力学变化。CYP2J2-EpOME轴代表了CRPC代谢导向的候选易感性，需要功能和临床验证。
期刊介绍：
The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area.
With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field.
Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.
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