Abstract 2362: Antimetastatic potential of the antiprogestin mifepristone in cancer cells

Abstract

Abstract For most cancers, it is metastasis and burden of the secondary tumors that account for nearly 90% of cancer-related mortality. The process of metastatic dissemination of tumor cells is extremely complex. Among the critical parameters involved in metastatic spread are cellular detachment from the initial tumor, migration, invasion and adhesion to secondary sites, all processes associated with changes in cell morphology caused by cytoskeletal rearrangements. Our laboratory previously demonstrated that the synthetic antiprogestin mifepristone (MF) inhibits the growth of cancer cells of reproductive and non-reproductive origin. We also observed that in response to MF, the cells displayed drastic changes in morphology. Due the impact of cell structure on the metastatic process, this study questioned whether MF has anti-metastatic potential deregulating key processes required for metastatic dissemination. Cancer cell lines of the ovary (SK-OV-3), breast (MDA-MB-231), prostate (LNCaP), and brain (U87MG) were chosen from a panel of cell lines in which we previously observed cytostatic activity of MF associated with changes in cellular morphology. Cell cultures were exposed to vehicle or MF for 72 h at which point we examined the morphology of the cells, the distribution of cytoskeletal proteins actin and tubulin, the adhesion capacity to components of the extracellular matrix, and the cell migratory and invasive properties. MF induced distinct morphology changes after 48 h exposure, independent of the density of the cell culture population. Interestingly, MF induced similar morphology changes in all cell lines, which included shrinkage of the cell body, long, thin cellular extensions, and a loss of cell-to-cell connections. Morphology changes were associated with rearrangement of actin and tubulin filaments. Upon removal of MF, cell morphology and proliferation returned to that of untreated cultures in all cell lines expect for LNCaP. For all cell lines, MF caused accelerated trypsin-induced detachment and decrease in cell adhesion to various extracellular matrix substrates suggesting that MF may impair re-adhesion of cells en route to colonize a secondary location. Moreover, MF significantly inhibited the ability of cells to migrate in wound healing and Boyden chamber assays, as well as their capacity to invade through extracellular matrix-coated polycarbonate membranes. Overall this study suggests that antiprogestin MF could be of potential therapeutic use, not only as a cytostatic agent impairing tumor growth, but also to halt metastatic spread of tumor cells. (Supported by NCI grants K22CA121991 and K22CA121991S1). 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 2362. doi:10.1158/1538-7445.AM2011-2362