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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.

SUBMITTER: Wei W

PROVIDER: S-EPMC4649509 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Project description:BackgroundOsteoarthritis (OA) is the most common joint disease worldwide, but its cause remains unclear. Oestrogen protects against OA, but its clinical use is limited. G protein-coupled receptor 30 (GPR30) is a receptor that binds oestrogen, and GPR30 treatment has benefitted patients with some degenerative diseases. However, its effects on OA prevention and treatment remain unclear. Moreover, several studies have found that activation of estrogen receptors exerting anti-ferroptosis effects, which plays an important role in chondrocyte survival. Therefore, this study explored the general and ferroptosis-related effects and mechanisms of GPR30 in OA.MethodsGenome-wide RNA sequencing, western blotting, and immunohistochemistry were used to evaluate GPR30 expression and ferroptosis-related indicators in cartilage tissues from clinical patients. Next, we investigated the effects of G1 (a GPR30 receptor agonist) on the function and pathology of OA in an animal model. We also treated chondrocytes with erastin (ferroptosis agonist) plus G1, G15 (GPR30 receptor antagonist), GPR30 short hairpin RNA, or ferrostatin-1 (ferroptosis inhibitor), then measured cell viability and ferroptosis-related indices and performed proteomics analyses. Finally, western blotting and reverse transcription-polymerase chain reaction were used to assess the effects of G1 on yes-associated protein 1 (YAP1) and ferritin heavy chain 1 (FTH1) expression.ResultsGPR30 expression was lower in the OA cartilage tissues than in the normal tissues, and G1 treatment significantly improved the locomotor ability of mice. Moreover, chondrocyte cell viability significantly decreased after erastin treatment, but G1 treatment concentration-dependently mitigated this effect. Furthermore, G1 treatment decreased phosphorylated YAP1 expression, increased activated YAP1 expression, and increased FTH1 transcription and protein expression, protecting against ferroptosis.ConclusionGPR30 activation inhibited ferroptosis in chondrocytes by suppressing YAP1 phosphorylation, which regulates FTH1 expression.The Translational Potential of this Article: These results provide a novel potential target for therapeutic OA interventions.

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

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