Periplocin potentiates ferroptotic cell death in non-small cell lung cancer by inducing the degradation of Nrf2.

IF 6 2区 医学 Q1 ONCOLOGY
Jinhao Wang, Yue Zhu, Jialiang Song, Fengping Yang, Peng Wang, Ziyi Zhang, Yuxuan Li, Minghe Dai, Yinuo Wang, Waleed Yousuf, Jiayu Li, Dian Yang, Shaoxuan Cheng, Shuyan Liu, Zhaoxia Dai, Xun Qiu, Yingqiu Zhang, Zengchun Hu
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Abstract

Background: Non-small cell lung cancer represents the main histological subtype of lung cancer. Periplocin is a major cardiac glycoside found in the traditional Chinese medicine Cortex periplocae administered in cardiovascular and autoimmune diseases. Inspired by recent findings reporting the anticancer activities of periplocin, this study investigates its potential effects against lung cancer.

Methods: The influence of periplocin on non-small cell lung cancer cells was examined by CCK-8, colony formation, and EdU staining assays, followed by transcriptomic profiling with RNA sequencing. Gene set enrichment analysis was conducted to identify pathways affected by periplocin. Nrf2 expression was assessed by Western blotting and turnover was investigated by cycloheximide chase assays. Cellular ferroptosis was induced by the GPX4 inhibitor with or without periplocin treatment. The in vivo effects of periplocin were assessed using lung cancer xenograft mouse models.

Results: Periplocin inhibited lung cancer cell growth in vitro. Transcriptomic analysis showed significant downregulation of Nrf2 downstream targets. Biochemical characterization revealed that periplocin increased Nrf2 turnover by promoting proteasomal degradation, leading to decreased levels of downstream transcripts. Functionally, Nrf2 reduction imposed by periplocin treatment rendered lung cancer cells increased susceptibility to ferroptosis induction. Finally, periplocin treatment demonstrated similar inhibition to restrict lung cancer xenograft growth as compared to the ferroptosis inducer imidazole ketone erastin, with both compounds leading to elevated expression of the ferroptosis marker COX2 in xenograft tumor tissues.

Conclusion: Our investigation suggests periplocin as a potential agent in the development of ferroptosis-inducing therapies against non-small cell lung cancer.

Periplocin通过诱导Nrf2的降解加速非小细胞肺癌的铁致细胞死亡。
背景:非小细胞肺癌是肺癌的主要组织学亚型。Periplocin是中药periplocae中发现的一种主要的心脏糖苷,用于心血管和自身免疫性疾病。受最近报道的periplocin抗癌活性的启发,本研究调查了其对肺癌的潜在作用。方法:采用CCK-8法、集落形成法、EdU染色法检测periplocin对非小细胞肺癌细胞的影响,并进行RNA测序转录组学分析。进行基因集富集分析以确定受periplocin影响的途径。Western blotting检测Nrf2的表达,环己亚胺追踪法检测细胞周转率。GPX4抑制剂加或不加periplocin均可诱导细胞铁下垂。使用肺癌异种移植小鼠模型评估了哌氯星的体内效应。结果:Periplocin对体外培养的肺癌细胞有抑制作用。转录组学分析显示Nrf2下游靶点显著下调。生化表征表明,periplocin通过促进蛋白酶体降解而增加Nrf2的周转,导致下游转录物水平下降。在功能上,吡氯星治疗导致的Nrf2降低使肺癌细胞对铁下垂诱导的易感性增加。最后,与铁下垂诱诱剂咪唑酮erastin相比,periplocin治疗在限制肺癌异种移植物生长方面表现出类似的抑制作用,这两种化合物都会导致铁下垂标志物COX2在异种移植物肿瘤组织中的表达升高。结论:我们的研究表明,在开发诱导铁凋亡治疗非小细胞肺癌的药物中,periplocin是一种潜在的药物。
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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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