Abstract
Cisplatin is the major chemotherapeutic drug in gastric cancer, particularly in treating advanced gastric cancer. Tumour cells often develop resistance to chemotherapeutic drugs, which seriously affects the efficacy of chemotherapy. GPR30 is a novel oestrogen receptor that is involved in the invasion, metastasis and drug resistance of many tumours. Targeting GPR30 has been shown to increase the drug sensitivity of breast cancer cells. However, few studies have investigated the role of GPR30 in gastric cancer. Epithelial‐mesenchymal transition (EMT) has been shown to be associated with the development of chemotherapeutic drug resistance. In this study, we demonstrated that GPR30 is involved in cisplatin resistance by promoting EMT in gastric cancer. GPR30 knockdown resulted in increased sensitivity of different gastric cancer (GC) cells to cisplatin and alterations in the epithelial/mesenchymal markers. Furthermore, G15 significantly enhanced the cisplatin sensitivity of GC cells while G1 inhibited this phenomenon. In addition, EMT occurred when AGS and BGC‐823 were treated with cisplatin. Down‐regulation of GPR30 with G15 inhibited this transformation, while G1 promoted it. Taken together, these results revealed the role of GPR30 in the formation of cisplatin resistance, suggesting that targeting GPR30 signalling may be a potential strategy for improving the efficacy of chemotherapy in gastric cancer.
Highlights
Gastric cancer (GC) is the fifth most common cancer in the world and the third leading cause of cancer deaths
The results indicated that GPR30 expression was significantly inhibited by G15 (Figure 2G,H), suggesting that G15 can increase the sensitivity of GC cells to cisplatin by inhibiting GPR30
Studies have reported that cisplatin is capable of inducing cell apoptosis, which is caused by cross-linking of intracellular DNA and DNA damage leading to regression of tumours; apoptosis can lead to increased expression of Epithelial-mesenchymal transition (EMT)-inducible factors and treatment failure.[29]
Summary
Gastric cancer (GC) is the fifth most common cancer in the world and the third leading cause of cancer deaths. The results of these studies are conflicting and controversial.[17,18,19] GPR30 is a seven-transmembrane domain protein that structurally differs from classical oestrogen receptors (ERα and ERβ) and significantly differs in terms of its mechanism and effect.[20,21] Binding of GPR30 to its ligand is known to cause rapid activation of many intracellular signal transduction pathways such as an increase in adenylate cyclase (cAMP), mobilization of intracellular calcium stores, transactivation of EGFR and activation of downstream signal transduction pathways such as PI3K/AKT and ERK1/2 These signalling pathways play an important role in the proliferation, metastasis and formation of drug resistance of human tumours.[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] few studies have investigated the effect of targeting GPR30 in gastric cancer. We aimed to investigate the role of GPR30 in the formation of cisplatin resistance in GC cells and to explore the potential of GPR30 as a therapeutic target for improving the efficacy of chemotherapy in GC
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