Carvacrol Selectively Induces Mitochondria-Related Apoptotic Signaling in Primary Breast Cancer-Associated...

Area of Science:

• Cancer Biology
• Molecular Pharmacology
• Cell Biology

Background:

• Cancer-associated fibroblasts (CAFs) are crucial in promoting breast tumor growth and therapy resistance.
• The effects of carvacrol, a dietary phenol, on CAFs are not well understood.
• Understanding carvacrol's impact on CAFs is vital for developing novel breast cancer therapies.

Purpose of the Study:

• To investigate if carvacrol selectively triggers apoptosis in breast CAFs.
• To determine if carvacrol affects normal fibroblasts (NFs) differently.
• To elucidate the molecular mechanisms underlying carvacrol's effects on CAFs.

Main Methods:

• Primary CAF and NF cultures were established and validated.
• Cells were treated with carvacrol (400 μM) and apoptosis was assessed via TUNEL assay and BAX/BCL-XL ratio.
• Signaling pathways (PPARα/NF-κB, sirtuins, autophagy markers, MMPs) and molecular interactions (caspase-3, -9) were analyzed using Western blotting, immunofluorescence, and in silico simulations.

Main Results:

• Carvacrol induced significant apoptosis in CAFs, decreasing viability and increasing the BAX/BCL-XL ratio.
• Normal fibroblasts showed minimal apoptosis and no significant change in BAX/BCL-XL ratio.
• Carvacrol modulated key pathways in CAFs, including PPARα/NF-κB, sirtuins, autophagy, and matrix metalloproteinases, consistent with mitochondria-related apoptosis.

Conclusions:

• Carvacrol selectively induces mitochondria-related apoptosis in breast CAFs, sparing normal fibroblasts.
• Carvacrol's action involves coordinated regulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways.
• Carvacrol shows potential as a microenvironment-targeted therapeutic adjunct for breast cancer.