Department of Biochemistry and Molecular Biology, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
Yiyang Key Laboratory of Chemical Small Molecule Anti-Tumor Targeted Therapy, Department of Scientific Research, Yiyang Medical College, Yiyang, 413000, China.
Sci Rep. 2024 Nov 19;14(1):28559. doi: 10.1038/s41598-024-79592-9.
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.
三阴性乳腺癌（TNBC）是乳腺癌中最恶性的分子亚型，其特点是侵袭性强、死亡率高、异质性显著、预后不良。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。在这里，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 选择性地抑制 TNBC 细胞在体外和体内的增殖。流式细胞术和 Western blot 分析显示，ZSW-4B 诱导 TNBC 细胞凋亡。磷酸蛋白质组学分析显示，ZSW-4B 激活了 AMPK 信号通路。此外，应用 CRISPR-Cas9 系统对 TNBC 细胞系中的 AMPK 进行基因敲除，证明其可逆转 ZSW-4B 在体外和体内的抗肿瘤作用。综上所述，ZSW-4B 通过激活 AMPK 诱导细胞凋亡来抑制 TNBC。
