Actin Cytoskeleton Participation in the Onset of IL-1β Induction of an Invasive Mesenchymal-like Phenotype in Epithelial MCF-7 Cells

Background: Interleukin 1 beta (IL-1β) and other inflammatory cytokines are reported to induce phenotypic changes in epithelial breast cancer tumor cells related to increased invasiveness. Mechanisms involved in the process are not well understood. Methods: The noninvasive breast cancer epithelial cell line MCF-7 was used to investigate the IL-1β-induced phenotype. Live cells expressing EGFP-actin were monitored for cell morphology changes and actin cytoskeleton dynamics by time-lapse video microscopy in the presence of IL-1β and specific inhibitors of actin signaling pathways. Chemotaxis, invasion of Matrigel, MMP activity and expression of S100A4 in cells treated with IL-1β were assessed by migration assays, zymograms and immunoblots. Results: Exposure to IL-1β specifically induced a change in MCF-7 cells from a typical epithelial morphology into elongated cells, showing numerous dynamic actin-rich lamellae and peripheral ruffles characteristic of fibroblasts. These cells could scatter from compact cell colonies and respond to chemoattractants such as the homing-associated chemokine CXCL-12. Pharmacological blockage of actin signaling pathways and negative mutants of RhoGTPases revealed that actin reorganization and enhanced motility are regulated via PI3K/Rac 1 activation. IL-1β-stimulated cells expressed the metastasis promoter S100A4, increased secretion of active MMP-9 and MMP-2 and invasion of extracellular matrix proteins. Conclusions: IL-1β induces a PI3K/Rac 1-regulated reorganization of the actin cytoskeleton of MCF-7 cells that is required for cell scattering, elongation and migration. The enhanced motility is accompanied by expression of protein markers correlated with invasive behavior.