Abstract
The G-protein-coupled estrogen receptor 1 (GPER) has recently been reported to mediate the non-genomic action of estrogen in different types of cells and tissues. G-1 (1-[4-(6-bromobenzo[1,3] dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) was developed as a potent and selective agonist for GPER. G-1 has been shown to induce the expression of genes and activate pathways that facilitate cancer cell proliferation by activating GPER. Here we demonstrate that G-1 has an anticancer potential with a mechanism similar to vinca alkaloids, the commonly used chemotherapy drugs. We found that G-1 blocks tubulin polymerization and thereby interrupts microtubule assembly in ovarian cancer cells leading to the arrest of cell cycle in the prophase of mitosis and the suppression of ovarian cancer cell proliferation. G-1 treatment also induces apoptosis of ovarian cancer cells. The ability of G-1 to target microtubules to suppress ovarian cancer cell proliferation makes it a promising candidate drug for treatment of ovarian cancer.
Highlights
Previously called GPR30 (G-protein-coupled receptor 30)) has important roles in many physiological actions in the body
The results show that G-1 is able to suppress IGROV-1 cell proliferation in a concentration-dependent manner (Figure 1a)
G-1 treatment induced apoptosis, as indicated by an increase in apoptotic cells in G-1-treated IGROV-1 and SKOV-3 cells (Figures 1b and d). These results reveal that the putative GPER agonist G-1 is able to promote cell-cycle progression to the S-phase and arrest ovarian cancer cells in the G2/M prophase, leading to suppression of ovarian cancer cell proliferation and induction of ovarian cancer cell apoptosis
Summary
Previously called GPR30 (G-protein-coupled receptor 30)) has important roles in many physiological actions in the body. G-1 was found to be incapable of activating the estrogen response element in the promoters of estrogen response genes at concentrations from 1 nM to 10 mM.[5] The specificity of G-1 was further confirmed by a study showing that G-1 does not significantly interact with 25 other G-protein-coupled receptors.[6] G-1 has been found to mobilize intracellular calcium in COS-7 cells that transiently expressed GPER and activate phosphatidylinositide 3-kinase in SKBr3 (ER À and GPER þ ) and MCF7 (ER þ and GPER þ ) breast cancer cells.[3,4] G-1 has been found to inhibit the chemoattractant-induced migration of SKBr3 and MCF7 cells.[3,4] The above mentioned characteristics make G-1 an excellent ligand to study GPER’s function under both physiological and pathological conditions. Both the function of GPER and the effect of G-1 on the proliferation of cancer cells require further investigation
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