PO.ET05.02 · 实验与分子治疗
抑制NRF2驱动的抗氧化防御与EMT是brusatol诱导宫颈癌细胞毒性的基础
Inhibition of NRF2 driven antioxidant defence and EMT underlies brusatol induced cytotoxicity in cervical cancer cells
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摘要 Abstract
中文摘要
宫颈癌仍是全球重大的健康负担，其治疗耐药性受到氧化还原适应、上皮-间质转化（EMT）及代谢重编程的强烈影响。Brusatol是一种天然苦木素类化合物，以其抑制NRF2驱动的抗氧化防御机制的能力而著称。然而，其对宫颈癌的机制性作用尚未得到充分阐明。在本研究中，我们首先采用定量蛋白质组学分析，以获得对Brusatol诱导的分子改变的无偏概览。蛋白质组学分析揭示了与抗氧化防御、糖酵解、细胞骨架组织及EMT调控相关的蛋白质广泛下调。相反，与氧化应激反应、线粒体功能障碍及凋亡信号传导相关的蛋白质显著上调。通路富集分析证实了糖酵解及氧化还原调节通路受到抑制、细胞运动网络受到抑制以及氧化应激驱动的细胞毒性过程被激活。这些整体蛋白质组学特征通过western blot验证得到进一步佐证，结果表明Brusatol处理后，参与抗氧化防御及EMT调控的关键组分表达降低。Western blot分析还显示糖酵解标志物受到抑制，支持了蛋白质组学预测的代谢紊乱。在功能层面，Brusatol在宫颈癌细胞系中显著降低了增殖、诱导了凋亡、抑制了迁移，并逆转了EMT特征。处理后的细胞表现出间质标志物表达降低、上皮特征恢复、葡萄糖摄取减少以及糖酵解活性受损。重要的是，一株非致瘤性上皮细胞系表现出显著更低的敏感性，表明其对癌细胞具有选择性细胞毒性。
综上所述，这些发现表明Brusatol通过启动广泛的蛋白质组学重编程、抑制NRF2相关的抗氧化通路、逆转EMT以及破坏糖酵解代谢，对宫颈癌发挥强效抗肿瘤作用。将蛋白质组学分析与生化验证及功能实验相结合，为brusatol作为克服宫颈癌治疗耐药性的有前景的治疗候选药物提供了有力的机制证据。
查看英文原文 English abstract
Cervical cancer remains a major global health burden, and its therapeutic resistance is strongly influenced by redox adaptation, epithelial-mesenchymal transition (EMT), and metabolic reprogramming. Brusatol, a natural quassinoid compound, is known for its ability to suppress NRF2-driven antioxidant defense mechanisms. However, its mechanistic impact on cervical cancer has not been fully characterized.In this study, we first employed quantitative proteomic profiling to obtain an unbiased overview of Brusatol-induced molecular alterations. Proteomics analysis revealed extensive downregulation of proteins associated with antioxidant defense, glycolysis, cytoskeletal organization, and EMT regulation. Conversely, proteins linked to oxidative stress responses, mitochondrial dysfunction, and apoptotic signalling were significantly upregulated. Pathway enrichment analysis confirmed inhibition of glycolytic and redox-regulatory pathways, suppression of cell motility networks, and activation of oxidative stress driven cytotoxic processes.These global proteomic signatures were further substantiated through western blot validation, which demonstrated reduced expression of key components involved in antioxidant defense and EMT regulation following Brusatol treatment. Western blot analysis also showed suppression of glycolytic markers, supporting the proteomics-predicted metabolic disruption.Functionally, Brusatol significantly reduced proliferation, induced apoptosis, suppressed migration, and reversed EMT characteristics in cervical cancer cell lines. Treated cells exhibited decreased mesenchymal marker expression, restoration of epithelial traits, reduced glucose uptake, and impaired glycolytic activity. Importantly, a non-tumorigenic epithelial cell line showed substantially lower sensitivity, indicating selective cytotoxicity toward cancer cells.
Together, these findings demonstrate that Brusatol exerts potent anti-tumor effects in cervical cancer by initiating widespread proteomic reprogramming, suppressing NRF2-linked antioxidant pathways, reversing EMT, and disrupting glycolytic metabolism. The integration of proteomic profiling with biochemical validation and functional assays provides strong mechanistic evidence supporting brusatol as a promising therapeutic candidate for overcoming treatment resistance in cervical cancer.
利益披露 Disclosure
G. Dagar, None..
M. U. Rehmani, None..
T. Haritwal, None..
M. Singh, None.