1-(4-(6-bromobenzo(1-3)dioxol-5-yl)-3a-4-5-9b-tetrahydro-3h-cyclopenta(c)quinolin-8-yl)ethanone and Neoplasm-Metastasis

Emerging evidences show that G-protein-coupled estrogen receptor (GPER) can regulate the progression of various cancers, while its roles in the progression of osteosarcoma (OS) are not well illustrated.. The expression of GPER in OS cells and tissues were checked. Its roles in cell migration and expression of Snail was checked by use of its agonist G-1.. We found that the expression of GPER in OS cells and tissues were lower than that in their corresponding controls. OS patients with higher levels of GPER showed increased overall survival rate (OS) as compared with the lower ones. The activator of GPER (G-1) or overexpression of GPER can inhibit the migration and invasion of OS cells and downregulate mesenchymal markers. G-1 can rapidly decrease the expression of Snail, one powerful epithelial-mesenchymal transition transcription factor (EMT-TF). Overexpression of Snail can attenuate the suppression effects of G-1 on migration of OS cells, suggesting that Snail was involved in GPER-regulated migration of OS cells. Mechanically, G-1 rapidly decreased the protein of Snail but had no effect on its mRNA expression. This was because G-1 can decrease the protein stability of Snail. Further, G-1 increased the expression of FBXL5, which can trigger the proteasome-mediated degradation of Snail. Knockdown of FBXL5 can reverse G-1-induced downregulation of Snail in OS cells.. Activation of GPER can suppress the migration and invasion of OS cells via FBXL5-mediated post-translational down regulation of Snail. It suggested that targeted activation of GPER might be a potent potential therapy approach to overcome the metastasis of OS patients.

Topics: Bone Neoplasms; Cell Line; Cell Line, Tumor; Cell Movement; Cyclopentanes; Disease Progression; Down-Regulation; Epithelial-Mesenchymal Transition; F-Box Proteins; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Osteosarcoma; Protein Processing, Post-Translational; Quinolines; Receptors, Estrogen; Receptors, G-Protein-Coupled; RNA, Messenger; Snail Family Transcription Factors; Survival Rate; Ubiquitin-Protein Ligase Complexes

Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC.

Topics: Androgens; Animals; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Chromatin Immunoprecipitation; Cohort Studies; Cyclopentanes; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Male; Mice; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Prostatic Neoplasms, Castration-Resistant; Quinolines; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Receptors, Estrogen; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tumor Cells, Cultured; Xenograft Model Antitumor Assays