The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo

Abstract

There is an urgent clinical need for safe and effective treatment agents and therapy targets for estrogen receptor negative (ER−) breast cancer. G protein-coupled receptor 30 (GPR30), which mediates non-genomic signaling of estrogen to regulate cell growth, is highly expressed in ER− breast cancer cells. We here showed that activation of GPR30 by the receptor-specific agonist G-1 inhibited the growth of ER− breast cancer cells in vitro. Treatment of ER− breast cancer cells with G-1 resulted in G2/M-phase arrest, downregulation of G2-checkpoint regulator cyclin B, and induction of mitochondrial-related apoptosis. The G-1 treatment increased expression of p53 and its phosphorylation levels at Serine 15, promoted its nuclear translocation, and inhibited its ubiquitylation, which mediated the growth arrest effects on cell proliferation. Further, the G-1 induced sustained activation and nuclear translocation of ERK1/2, which was mediated by GPR30/epidermal growth factor receptor (EGFR) signals, also mediated its inhibition effects of G-1. With extensive use of siRNA-knockdown experiments and inhibitors, we found that upregulation of p21 by the cross-talk of GPR30/EGFR and p53 was also involved in G-1-induced cell growth arrest. In vivo experiments showed that G-1 treatment significantly suppressed the growth of SkBr3 xenograft tumors and increased the survival rate, associated with proliferation suppression and upregulation of p53, p21 while downregulation of cyclin B. The discovery of multiple signal pathways mediated the suppression effects of G-1 makes it a promising candidate drug and lays the foundation for future development of GPR30-based therapies for ER− breast cancer treatment.

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

“…4A). In line with the previous studies [26-28], the dose of 1μM G-1 was selected for further in vitro studies. Furthermore, we conducted knockdown assays in MDA-MB-231 cells to assess whether the inhibitory effects of G-1 depended on GPER activation.…”

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…GPER mediates the activation of a network of transduction pathways; however, the actual role elicited by GPER in tumorigenesis is still controversial. Previous studies have shown that GPER may induce cell cycle arrest and inhibition of cancer cell growth (13)(14)(15)(16). Nevertheless, other in vitro and in vivo studies have revealed that GPER triggers cancer cell migration and proliferation (5,17).…”

Development and optimization of G-1 polymeric nanoparticulated and liposomal systems for central nervous system applications

“…It has been demonstrated that G-1 improves the cognitive abilities and social learning of mice [24,25]. It may also possess anxiolytic potential in mice [26,27]; and potential antineoplasic effects, as it is capable of inhibiting the proliferation of cervical, adrenocortical carcinoma and breast tumor cells [28][29][30]. G-1 has also anti-inflammatory properties, raising T regulatory cell population and IL-10 secretion [31,32].…”