1. G protein-coupled estrogen receptor-1 agonist induces chemotherapeutic effect via ER stress signaling in gastric cancer.
- Author
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Lee SJ, Kim TW, Park GL, Hwang YS, Cho HJ, Kim JT, and Lee HG
- Subjects
- Animals, Breast Neoplasms genetics, Cell Line, Tumor, Cell Proliferation drug effects, Cyclopentanes metabolism, Endoplasmic Reticulum Stress physiology, Estrogens metabolism, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Mice, Mice, Nude, Quinolines metabolism, Receptors, G-Protein-Coupled agonists, Signal Transduction drug effects, Stomach Neoplasms metabolism, Tamoxifen pharmacology, Xenograft Model Antitumor Assays, Cyclopentanes pharmacology, Quinolines pharmacology, Receptors, Estrogen metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
G protein-coupled estrogen receptor (GPER) is known to play an important role in hormone-associated cancers. G-1, a novel synthetic GPER agonist, has been reported to exhibit anti-carcinogenic properties. However, the chemotherapeutic mechanism of GPER is yet unclear. Here, we evaluated GPER expression in human gastric cancer tissues and cells. We found that G-1 treatment attenuates GPER expression in gastric cancer. GPER expression increased G-1-induced antitumor effects in mouse xenograft model. We analyzed the effects of knockdown/overexpression of GPER on G-1-induced cell death in cancer cells. Increased GPER expression in human gastric cancer cells increased G-1-induced cell death via increased levels of cleaved caspase-3, -9, and cleaved poly ADP-ribose polymerase. Interestingly, during G-1-induced cell death, GPER mRNA and protein expression was attenuated and associated with ER stress-induced expression of PERK, ATF-4, GRP-78, and CHOP. Furthermore, PERK-dependent induction of ER stress activation increased G-1-induced cell death, whereas PERK silencing decreased cell death and increased drug sensitivity. Taken together, the data suggest that the induction of ER stress via GPER expression may increase G-1-induced cell death in gastric cancer cells. These results may contribute to a new paradigm shift in gastric cancer therapy. [BMB Reports 2019; 52(11): 647-652].
- Published
- 2019