Abstract 4546: Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression

Abstract

Abstract The synthetic steroid hormone mifepristone (MF) was originally developed as a glucocorticoid receptor (GR) antagonist, but the capacity of this compound to modulate the activity of the progesterone receptor (PR) led to an intensive study of its potential applications as an antiprogestin. The emphasis on the interaction between MF and PR has been translated to its application as a potential therapeutic agent in the field of oncology; however, it remains unclear whether the expression of PR is required for MF to act as anti-cancer agent. Our laboratory has previously shown that MF is a potent inhibitor of ovarian cancer (OvCa) cell growth, and that the cytostatic action of MF occurs through an arrest in the G1 phase of the cell cycle characterized by a decrease in cyclin dependent kinase (Cdk) 2 activity. In this study, we questioned whether the growth inhibitory properties of MF observed in OvCa cells would be effectively translated to other cancers of reproductive and non-reproductive origin, and, importantly, whether the efficacy of MF as an antiproliferative agent was dependent upon PR expression. Dose-response experiments were conducted with a panel of cancer cell lines of the brain (meningioma IOMM-Lee and glioblastoma U87MG cells), breast (estradiol-responsive MCF-7 and estradiol-unresponsive MDA-MB-231 cells), prostate (androgen-responsive LNCaP and androgen-unresponsive PC-3 cells), ovary (OVCAR-3 and SK-OV-3 cells), and bone (osteosarcoma U-2OS and SAOS-2 cells). Cultures were exposed to vehicle or increasing concentrations of MF for 72 h and then analyzed for cell number and cell cycle traverse. For all cell lines, expression of steroid hormone receptors and cell cycle regulatory proteins controlling the G1-S phase transition in cells treated with vehicle or MF for 24 h was studied by Western blot analysis. The activity of Cdk2 in both treatment groups was monitored in vitro by the capacity of Cdk2 to phosphorylate its substrate histone H1. MF growth inhibited all cancer cell lines included in this study, regardless of tissue of origin and hormone responsiveness. Changes in the abundance of the cell cycle regulatory proteins p21cip1, p27kip1, cyclin E, and Cdk2 along with changes in Cdk2 activity following 24 h exposure to MF suggested that MF induces a G1 phase arrest in the majority of these cell lines, consistent with our previous results in OvCa cells. Importantly, studies of the basal expression of steroid hormone receptors in this panel of cell lines showed that while all cell lines were growth inhibited by MF, only MCF-7 cells expressed PR. This study supported our previous results with MF-treated OvCa cells suggesting a mechanism of action involving G1 arrest and a corresponding decrease in Cdk2 activity. Contrary to common opinion, growth inhibition of this panel of cancer cell lines by MF was not dependent upon PR expression. NCI K22CA121991. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4546. doi:10.1158/1538-7445.AM2011-4546