11-Methoxytabersonine Induces Ferroptosis in Triple-Negative Breast Cancer via YY1-CDKL1-GPX4 Axis

Area of Science:

• Pharmacology and Toxicology
• Oncology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to limited targeted treatment options.
• Natural compounds are increasingly explored for their anti-cancer properties and novel mechanisms of action.
• 11-Methoxytabersonine (11-MT), a monoterpenoid-indole alkaloid from Melodinus henryi, has demonstrated potential anti-cancer activity.

Purpose of the Study:

• To evaluate the anti-tumor efficacy of 11-Methoxytabersonine (11-MT) against triple-negative breast cancer (TNBC).
• To elucidate the molecular mechanisms underlying 11-MT's anti-cancer effects, focusing on ferroptosis induction.
• To investigate the role of the YY1-CDKL1-GPX4 signaling axis in 11-MT's therapeutic action.

Main Methods:

• In vitro assays (CCK-8, colony formation, flow cytometry) assessed TNBC cell proliferation, cell cycle, and death.
• In vivo studies utilized a TNBC xenograft mouse model to evaluate anti-tumor efficacy and safety.
• Mechanistic studies included transmission electron microscopy (TEM), reactive oxygen species (ROS) detection, mitochondrial membrane potential (MMP) assays, and molecular analyses (GPX4, YY1, CDKL1 expression, Co-IP, ChIP).

Main Results:

• 11-MT significantly inhibited TNBC cell proliferation, induced cell cycle arrest, and promoted apoptosis in vitro.
• In vivo, 11-MT suppressed tumor growth in xenograft models with no significant organ toxicity.
• 11-MT induced ferroptosis by downregulating glutathione peroxidase 4 (GPX4) via the transcription factor Yin Yang 1 (YY1) and cyclin-dependent kinase-like 1 (CDKL1) pathway, leading to ROS accumulation.

Conclusions:

• 11-Methoxytabersonine (11-MT) exhibits potent anti-tumor activity against triple-negative breast cancer (TNBC).
• The anti-cancer effects are mediated by the induction of ferroptosis through the YY1-CDKL1-GPX4 signaling axis.
• 11-MT represents a promising novel therapeutic agent for TNBC treatment.