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Mol. Cell. Biol. doi:10.1128/MCB.02238-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities

From the Université de Reims Champagne-Ardenne (URCA), Laboratoire de Biochimie, CNRS UMR 6198, Moulin de la Housse, Reims, France; the Cell Biology Unit, de Duve Institute and Université catholique de Louvain, Brussels, Belgium

^* To whom correspondence should be addressed. Email: stephane.dedieu{at}univ-reims.fr.

	Abstract

The scavenger receptor, low density lipoprotein receptor-related protein-1 (LRP-1), mediates the clearance of a variety of biological molecules from the pericellular environment, including proteinases which degrade the extracellular matrix in cancer progression. However, its accurate functions remain poorly explored and highly controversial. Here we show that LRP-1 silencing by RNA interference results in a drastic inhibition of cell invasion despite a strong stimulation of pericellular MMP-2 and uPA proteolytic activities. Cell migration in both two- and three-dimensions is decreased by LRP-1 silencing. LRP-1-silenced carcinoma cells, which are characterized by major cytoskeleton rearrangements, display atypical overspread morphology with a lack of membrane extensions. LRP-1 silencing accelerates cell attachment, inhibits cell-substrate deadhesion, and induces the accumulation, at the cell periphery, of abundant talin-containing focal adhesion complexes deprived of FAK and paxillin. We conclude that, in addition to its role in ligand binding and endocytosis, LRP-1 regulates cytoskeletal organization and adhesive complexes turnover in malignant cells by modulating the focal complexes composition, thereby promoting invasion.