Naphthoquinone Derivative ZSW-4B Induces Apoptosis in Triple-negative Breast Cancer via AMPK signal Activation

Abstract Triple-negative breast cancer (TNBC) is the most malignant molecular subtype of breast cancer characterized by its strong aggressiveness, high mortality, significant heterogeneity, and poor prognosis. AMPK plays a critical role in maintain cellular energy balance, and its inactivation is associated with the malignancy breast cancer. Here, we identified the pharmacological mechanism of the 1, 4-naphthoquinone derivative ZSW-4B. The MTT assay, colony formation as-say, and nude mouse xenograft tumor model demonstrated that ZSW-4B selectively inhibits the proliferation of TNBC cells in both vitro and vivo. Flow cytometry and Western blot analysis revealed that ZSW-4B induces apoptosis in TNBC cells. Phosphoproteomics analysis unveiled the activation of the AMPK signaling pathway by ZSW-4B, and the application of the CRISPR-Cas9 system to genetically knockout AMPK in TNBC cell lines markedly reversed the anti-tumor effects elicited by ZSW-4B, both in vitro and in vivo. In summary, ZSW-4B inhibits TNBC by inducing cell apoptosis through the activation of the AMPK.