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

G-1, a G protein-coupled Estrogen receptor (GPER)-specific agonist, exhibits Anticancer potential in breast Cancer cells. This study aims to explore the molecular basis of Apoptosis induced by G-1 in MCF-7 and MDA-MB-231 breast Cancer cells. Here, we found that G-1 induced cytotoxicity and GPER-dependent Apoptosis with PARP cleavage and mitochondrial membrane potential (MMP) loss, as well as nuclear condensation. Fluorescence resonance energy transfer (FRET) analysis in living cells indicated that G-1 effectively disrupted the interaction between large tumor suppressor 1/2 (LATS1/2) and Yes-associated protein (YAP). Furthermore, G-1 reduced YAP phosphorylation levels and promoted its nuclear accumulation. Notably, knockdown of YAP attenuated G-1-induced Apoptosis, highlighting the crucial role of YAP in this process. Additionally, FRET analysis revealed that G-1 enhanced the binding of YAP to p73, leading to an increase in Bcl-2-associated X protein (Bax) expression and an induction of Apoptosis. In summary, our findings demonstrate that G-1 induces Apoptosis through the GPER/YAP/p73-mediated pathway.