CDKN3 promoted triple-negative breast cancer by inhibiting ferroptosis through the upregulation of HSP90

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2026-01-01 Epub Date: 2025-11-07 DOI:10.1016/j.taap.2025.117629

Qiqi Zhao , Yufang Wang

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引用次数: 0

Abstract

Purpose

The study aimed to investigate CDKN3 as a potential target for triple negative breast cancer (TNBC) and its mechanism in this type of cancer.

Methods

After lentiviral transfection, various assays, including CCK8, clonogenic assay, flow cytometry, transwell, and scratch tests were conducted. Additionally, we examined CDKN3's impact on iron-induced cell death through various cellular markers and iron-related proteins. To assess CDKN3's impact on ferroptosis, we utilized the ferroptosis inhibitor Ferrostatin-1 and activator Erastin. To examine CDKN3's involvement in iron-induced cell death in TNBC, we repeated the previous experiment after introducing an HSP90 inhibitor. A 4T1 mammary fat pad graft tumor model was also conducted to validate the results of our in vitro cellular experiments.

Results

In vitro experiments demonstrated that overexpression of CDKN3 promoted the growth, invasion, and migration of breast cancer cells. It also facilitated cell cycle progression from G0/G1 phase to S phase and suppressed apoptosis in TNBC cells. The knockdown of CDKN3 was the exact opposite. Overexpression of CDKN3 increased HSP90 expression, while CDKN3 knockdown decreased HSP90 expression. The impact of CDKN3 on the proliferation, migration, invasion, and ferroptosis of TNBC cells was associated with HSP90. The in vivo and in vitro experimental results were consistent, showing that CDKN3 overexpression promoted tumor growth and inhibited ferroptosis.

Conclusion

CDKN3 was an oncogene whose overexpression promoted the initiation and progression of TNBC by inhibiting HSP90-mediated ferroptosis.

查看原文本刊更多论文

CDKN3通过上调HSP90抑制铁下垂促进三阴性乳腺癌。

目的：本研究旨在探讨CDKN3作为三阴性乳腺癌（TNBC）的潜在靶点及其在该类型癌症中的作用机制。方法：慢病毒转染后进行CCK8、克隆实验、流式细胞术、transwell、划痕试验等检测。此外，我们通过各种细胞标记物和铁相关蛋白检测了CDKN3对铁诱导的细胞死亡的影响。为了评估CDKN3对铁下垂的影响，我们使用了铁下垂抑制剂Ferrostatin-1和激活剂Erastin。为了研究CDKN3在TNBC中铁诱导的细胞死亡中的作用，我们在引入HSP90抑制剂后重复了之前的实验。为了验证我们的体外细胞实验结果，我们还建立了4T1乳腺脂肪垫移植瘤模型。结果：体外实验表明，CDKN3过表达可促进乳腺癌细胞的生长、侵袭和迁移。它还促进了TNBC细胞从G0/G1期向S期的细胞周期进展，抑制了TNBC细胞的凋亡。CDKN3基因的敲除则完全相反。CDKN3过表达增加HSP90表达，而CDKN3敲低降低HSP90表达。CDKN3对TNBC细胞增殖、迁移、侵袭和铁凋亡的影响与HSP90有关。体内和体外实验结果一致，表明CDKN3过表达促进肿瘤生长，抑制铁下垂。结论：CDKN3是一个癌基因，其过表达通过抑制hsp90介导的铁凋亡促进TNBC的发生和发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.