Z-Guggulsterone Inhibits Triple-Negative Breast Cancer Progression by Blocking Autophagosome-Lysosome Fusion via...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and lack of targeted treatments.
• Natural products offer a promising avenue for developing novel anticancer agents.

Purpose of the Study:

• To investigate the antitumor effects of Z-guggulsterone (Z-GS) in TNBC.
• To elucidate the underlying molecular mechanisms, focusing on autophagy and the OGT-SNAP29 signaling pathway.

Main Methods:

• In vitro studies using TNBC cell lines (MDA-MB-231, MDA-MB-468) assessed proliferation, cell cycle, apoptosis, and reactive oxygen species (ROS).
• Autophagic flux and OGT-SNAP29 signaling were analyzed using Western blotting, immunofluorescence, molecular docking, and molecular dynamics simulations.
• In vivo efficacy and safety were evaluated in TNBC xenograft models using zebrafish and BALB/c nude mice.

Main Results:

• Z-GS demonstrated selective suppression of TNBC cell proliferation, induced cell-cycle arrest, promoted apoptosis, and increased intracellular ROS.
• Z-GS upregulated O-GlcNAc transferase (OGT), enhanced SNAP29 O-GlcNAcylation, disrupted SNARE complex assembly, and inhibited late-stage autophagic flux.
• In vivo, Z-GS significantly inhibited tumor growth in xenograft models with no observable toxicity.

Conclusions:

• Z-guggulsterone acts as a novel inhibitor of late-stage autophagy.
• Z-GS exhibits selective anti-TNBC activity, representing a potential therapeutic strategy by combining natural product pharmacology with cancer treatment.