Decrease of breast cancer cell invasiveness by sodium phenylacetate (NaPa)is associated with an increased expression of adhesive molecules

Sodium phenylacetate (NaPa), a non-toxic phenylalanine metabolite, has been shown to induce in vivo and in vitro cytostatic and antiproliferative effe cts on various cell types. In this work, we analysed the effect of NaPa on the invasiveness of breast cancer cell (MDA-MB-231, MCF-7 and MCF-7 ras). U sing the highly invasive breast cancer cell line MDA-MB-231, we demonstrate d that an 18-hour incubation with NaPa strongly inhibits the cell invasiven ess through Matrigel (86% inhibition at 20 mM of NaPa). As cell invasivenes s is greatly influenced by the expression of urokinase (u-PA) and its cell surface receptor (u-PAR) as well as the secretion of matrix metalloproteina ses (MMP), we tested the effect of NaPa on these parameters. An 18-hour inc ubation with NaPa did not modify u-PA expression, either on MDA-MB-231 or o n MCF-7 and MCF-7 ras cell lines, and induced a small u-PA decrease after 3 days of treatment of MDA-MB-321 with NaPa, In contrast, an 18 h incubation of MDA-MB-231 increased the expression of U-PAR and the secretion of MMP-9 . As u-PAR is a ligand for vitronectin, a composant of the extracellular ma trix, these data could explain the increased adhesion of MDA-MB-231 to vitr onectin, while cell adhesivity of MCF-7 and MCF-7 ras was unmodified by NaP a treatment, NaPa induced also an increased expression of both Lymphocyte F u nction-Associated-1 (LFA-1) and Intercellular Adhesion Molecule-1 (ICAM-1 ), which was obvious from 18 hour incubation with NaPa for the MDA-MB-231 c ells, but was delayed (3 days) for MCF-7 and MCF-7 ras. Only neutralizing a ntibodies against LFA-I reversed the decreased invasiveness of NaPa-treated cells. Therefore we can conclude that the strong inhibition of MDA-MB-231 invasiveness is not due to a decrease in proteases involved in cell migrati on (u-PA and MMP) but could be related both to the modification of cell str ucture and an increased expression of adhesion molecules such as u-PAR and LFA-1. (C) 2001 Cancer Research Campaign http://www.bjcancer.com.