Naphthoquinone-derived ZSW-4B induces apoptosis in triple-negative breast cancer via AMPK signalling activation
Xiyuan Hu1, Hongdou Liu1,2, Tiao Luo3
1Department of Biochemistry and Molecular Biology, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
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.
Insights
The novel compound ZSW-4B effectively inhibits triple-negative breast cancer (TNBC) by inducing apoptosis. This occurs through the activation of the AMPK signaling pathway, offering a potential new therapeutic strategy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis.
- AMP-activated protein kinase (AMPK) pathway dysregulation is linked to breast cancer malignancy.
Purpose of the Study:
- To elucidate the pharmacological mechanism of the 1,4-naphthoquinone derivative ZSW-4B against TNBC.
- To investigate the role of AMPK activation in ZSW-4B's anti-TNBC effects.
Main Methods:
- In vitro assays (MTT, colony formation) and in vivo xenograft models were used to assess ZSW-4B efficacy.
- Flow cytometry, Western blot, and phosphoproteomic analysis were employed to determine molecular mechanisms.
- CRISPR-Cas9 was used to genetically knockout AMPK in TNBC cells.
Main Results:
- ZSW-4B selectively inhibited TNBC cell proliferation in vitro and in vivo.
- ZSW-4B treatment induced apoptosis in TNBC cells.
- ZSW-4B activated the AMPK signaling pathway, and AMPK knockout reversed its anti-tumor effects.
Conclusions:
- ZSW-4B demonstrates potent anti-TNBC activity by inducing apoptosis.
- Activation of the AMPK pathway is crucial for ZSW-4B's therapeutic efficacy.
- ZSW-4B represents a promising therapeutic candidate for TNBC treatment.
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