G-Protein-Coupled Estrogen Receptor Antagonist G15 Decreases Estrogen-Induced Development of Non-Small Cell Lung Cancer

Abstract

G-protein-coupled estrogen receptor (GPER) was found to promote non-small cell lung cancer (NSCLC) by estrogen, indicating the potential necessity of inhibiting GPER by a selective antagonist. This study was performed to elucidate the function of GPER-selective inhibitor G15 in NSCLC development. Cytoplasmic GPER (cGPER) and nuclear GPER (nGPER) were detected by immunohistochemical analysis in NSCLC samples. The relation of GPER and estrogen receptor β (ERβ) expression and correlation between GPER, ERβ, and clinical factors were analyzed. The effects of activating GPER and function of G15 were analyzed in the proliferation of A549 and H1793 cell lines and development of urethane-induced adenocarcinoma. Overexpression of cGPER and nGPER was detected in 80.49% (120/150) and 52.00% (78/150) of the NSCLC samples. High expression of GPER was related with higher stages, poorer differentiation, and high expression of ERβ. The protein level of GPER in the A549 and H1793 cell lines was increased by treatment with E2, G1 (GPER agonist), or fulvestrant (Ful; ERβ antagonist) and decreased by G15. Administration with G15 reversed the E2- or G1-induced cell growth by inhibiting GPER. In urethane-induced adenocarcinoma mice, the number of tumor nodules and tumor index increased in the E2 or G1 group and decreased by treatment with G15. These findings demonstrate that using G15 to block GPER signaling may be considered as a new therapeutic target in NSCLC.

Cisplatin resistance in gastric cancer cells is involved with GPR30‐mediated epithelial‐mesenchymal transition

“…G15 and G1 are GPR30‐specific antagonists and agonists, respectively, with no affinity for ERα and ERβ. They have been shown to have potential to treat tumours that express GPR30 . Due to the bidirectional nature of GPR30 on tumour growth, G15 limits the progression of non‐small cell lung cancer (NSCLC) by inhibiting GPR30 signalling .…”

“…They have been shown to have potential to treat tumours that express GPR30 . Due to the bidirectional nature of GPR30 on tumour growth, G15 limits the progression of non‐small cell lung cancer (NSCLC) by inhibiting GPR30 signalling . G1 inhibits the growth of prostate tumour cells in vivo and in vitro by activating GPR30 signalling .…”

“…24,25 Due to the bidirectional nature of GPR30 on tumour growth, G15 limits the progression of non-small cell lung cancer (NSCLC) by inhibiting GPR30 signalling. 25 G1 inhibits the growth of prostate tumour cells in vivo and in vitro by activating GPR30 signalling. 30 These studies suggest that targeting GPR30 may be a potential target for treating cancer more efficiently.…”

“…These signalling pathways play an important role in the proliferation, metastasis and formation of drug resistance of human tumours . G1 (GPR30 agonist) and G15 (GPR30 inhibitor) are quinoline derivatives that are widely used to activate or block GPR30 signalling and are used to explore the potential of GPR30 as a therapeutic target . A recent study showed that targeting GPR30 reduced metastasis and drug resistance in breast cancer .…”

“…22,23 G1 (GPR30 agonist) and G15 (GPR30 inhibitor) are quinoline derivatives that are widely used to activate or block GPR30 signalling and are used to explore the potential of GPR30 as a therapeutic target. 24,25 A recent study showed that targeting GPR30 reduced metastasis and drug resistance in breast cancer. 26 However, few studies have investigated the effect of targeting GPR30 in gastric cancer.…”