Naphthoquinone-derived ZSW-4B induces apoptosis in triple-negative breast cancer via AMPK signalling activation.

IF 3.8 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Xiyuan Hu, Hongdou Liu, Tiao Luo, Ling Chen, Ting Peng, Min Wen, Wensong Luo, Qunfang Xu, Yuanzhu Xie, Mo Li, Mingquan Liu, Xiaohe Liu, Suyou Liu, Shuaiwen Zhu, Zizheng Zou, Zhiyong Luo
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Abstract

Triple-negative breast cancer (TNBC) is the most malignant molecular subtype of breast cancer and is characterized by aggressiveness, high mortality, significant heterogeneity, and poor prognosis. AMPK plays a critical role in maintaining the cellular energy balance, and its inactivation is associated with malignant breast cancer. Here, we identified the pharmacological mechanism of the 1,4-naphthoquinone derivative ZSW-4B. MTT, colony formation, and nude mouse xenograft tumour models demonstrated that ZSW-4B selectively inhibits the proliferation of TNBC cells both in vitro and in vivo. Flow cytometry and Western blot analysis revealed that ZSW-4B induces apoptosis in TNBC cells. Phosphoproteomic analysis revealed activation of the AMPK signalling pathway by ZSW-4B. Additionally, the application of the CRISPR-Cas9 system to genetically knockout AMPK in TNBC cell lines was demonstrated to reverse the antitumour effects elicited by ZSW-4B both in vitro and in vivo. In summary, ZSW-4B inhibits TNBC by inducing cellular apoptosis through the activation of AMPK.

萘醌衍生的 ZSW-4B 通过激活 AMPK 信号诱导三阴性乳腺癌细胞凋亡。
三阴性乳腺癌(TNBC)是恶性程度最高的乳腺癌分子亚型,具有侵袭性强、死亡率高、异质性大和预后差等特点。AMPK 在维持细胞能量平衡方面起着关键作用,其失活与恶性乳腺癌有关。在此,我们确定了 1,4-萘醌衍生物 ZSW-4B 的药理机制。MTT、集落形成和裸鼠异种移植肿瘤模型表明,ZSW-4B 在体外和体内都能选择性地抑制 TNBC 细胞的增殖。流式细胞术和 Western 印迹分析表明,ZSW-4B 能诱导 TNBC 细胞凋亡。磷酸蛋白组分析显示,ZSW-4B 激活了 AMPK 信号通路。此外,应用 CRISPR-Cas9 系统在 TNBC 细胞系中基因敲除 AMPK,证明可以逆转 ZSW-4B 在体外和体内引起的抗肿瘤效应。总之,ZSW-4B 通过激活 AMPK 诱导细胞凋亡,从而抑制 TNBC。
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来源期刊
Scientific Reports
Scientific Reports Natural Science Disciplines-
CiteScore
7.50
自引率
4.30%
发文量
19567
审稿时长
3.9 months
期刊介绍: We publish original research from all areas of the natural sciences, psychology, medicine and engineering. You can learn more about what we publish by browsing our specific scientific subject areas below or explore Scientific Reports by browsing all articles and collections. Scientific Reports has a 2-year impact factor: 4.380 (2021), and is the 6th most-cited journal in the world, with more than 540,000 citations in 2020 (Clarivate Analytics, 2021). •Engineering Engineering covers all aspects of engineering, technology, and applied science. It plays a crucial role in the development of technologies to address some of the world''s biggest challenges, helping to save lives and improve the way we live. •Physical sciences Physical sciences are those academic disciplines that aim to uncover the underlying laws of nature — often written in the language of mathematics. It is a collective term for areas of study including astronomy, chemistry, materials science and physics. •Earth and environmental sciences Earth and environmental sciences cover all aspects of Earth and planetary science and broadly encompass solid Earth processes, surface and atmospheric dynamics, Earth system history, climate and climate change, marine and freshwater systems, and ecology. It also considers the interactions between humans and these systems. •Biological sciences Biological sciences encompass all the divisions of natural sciences examining various aspects of vital processes. The concept includes anatomy, physiology, cell biology, biochemistry and biophysics, and covers all organisms from microorganisms, animals to plants. •Health sciences The health sciences study health, disease and healthcare. This field of study aims to develop knowledge, interventions and technology for use in healthcare to improve the treatment of patients.
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