GPER agonist G-1 activates YAP to induce apoptosis in breast cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• G protein-coupled estrogen receptor (GPER) agonists show promise as anticancer agents.
• Understanding the molecular mechanisms of GPER-mediated apoptosis in breast cancer is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the molecular pathways through which G-1 induces apoptosis in human breast cancer cells (MCF-7 and MDA-MB-231).
• To investigate the role of the Yes-associated protein (YAP) and p73 in G-1-induced cell death.

Main Methods:

• Cell viability assays and apoptosis markers (PARP cleavage, mitochondrial membrane potential loss, nuclear condensation) were assessed.
• Fluorescence resonance energy transfer (FRET) was used to study protein-protein interactions in living cells.
• Western blotting and knockdown experiments were performed to evaluate protein expression and function.

Main Results:

• G-1 induced GPER-dependent apoptosis, characterized by PARP cleavage, loss of mitochondrial membrane potential, and nuclear condensation.
• G-1 disrupted the LATS1/2-YAP interaction, reduced YAP phosphorylation, and promoted YAP nuclear accumulation.
• YAP knockdown abrogated G-1-induced apoptosis, confirming YAP's essential role.
• G-1 enhanced YAP-p73 binding, increasing Bax expression and promoting apoptosis.

Conclusions:

• G-1 induces apoptosis in breast cancer cells via a GPER-dependent pathway.
• The GPER/YAP/p73 signaling axis is critical for G-1-mediated anticancer effects.
• Targeting the GPER/YAP/p73 pathway may represent a novel therapeutic strategy for breast cancer.