Abstract
BackgroundWe previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1. This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. This study aimed to determine whether arcyriaflavin A, a representative inhibitor of cyclin D1–cyclin-dependent kinase 4 (CDK4), is beneficial in the treatment of endometriosis.MethodsECSCs were isolated from the ovarian endometriotic tissues of 32 women. The effects of arcyriaflavin A on cell viability and proliferation, vascular endothelial growth factor A expression, apoptosis, and cell cycle progression were evaluated using a modified methylthiazoletetrazolium assay, enzyme-linked immunosorbent assay (ELISA), Caspase-Glo® 3/7 assay, and flow cytometry.ResultsArcyriaflavin A significantly inhibited cell viability, proliferation, and angiogenesis of ECSCs as assessed using the 5-bromo-2-deoxyuridine (BrdU) and methylthiazoletetrazolium bromide (MTT) assays, and vascular endothelial growth factor (VEGF) ELISA. Arcyriaflavin A induced apoptosis as shown in the Caspase-Glo® 3/7 assay and cell death detection ELISA whilethe cell cycle was arrested at the G0/G1 phase.ConclusionThe findings indicate that cyclin D1–CDK4 inhibitors may be promising candidates for the treatment of endometriosis. This is the first study to demonstrate the potential usefulness of arcyriaflavin A as a therapeutic agent for endometriosis. Further studies of the effects of cyclin D1–CDK4 inhibitors on endometriosis may provide useful information on pathogenesis and treatment.
Highlights
We previously showed that microRNA-503 transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1
To identify the mechanisms underlying the pathogenesis of endometriosis, our research has focused on the dysregulation of the expression of several microRNAs involved in endometriosis [4,5,6]. miRNAs, which regulate the translation of specific targeted protein-coding genes, are short noncoding RNAs
Isolated ECSCs were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 100 IU/mL penicillin, 50 mg/mL streptomycin, and 10% heatinactivated fetal bovine serum (FBS, all obtained from Gibco-BRL, Gaithersburg, MD, USA) at 37 °C in air containing 5% CO2
Summary
We previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1 This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. The transfection of miR-503 into ECSCs induces apoptosis by B-cell lymphoma-2 (Bcl-2) suppression, inhibition of vascular endothelial growth factor A (VEGF-A) production and cell proliferation, and induction of cell cycle arrest at the G0/ G1 phase by cyclin D1 suppression [5]. These findings prompted us to evaluate the therapeutic effects of cyclin D1 inhibitors on endometriotic cells
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