LRP-1 Silencing Prevents Malignant Cell Invasion despite Increased Pericellular Proteolytic Activities

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 matrix metalloproteinase 2 and urokinase-type plasminogen activator 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 complex turnover in malignant cells by modulating the focal complex composition, thereby promoting invasion.

ACKNOWLEDGMENTS

This work was supported by grants from CNRS and Fonds National pour la Santé ACI 2004 and ACI 2008 (Cancéropôle Grand-Est project). P. Henriet is a research associate at the Belgian FNRS.

We thank H. Kaplan and L. Parent for technical assistance. We are grateful to D. K. Strickland (American Red Cross, Rockville, MD) for kindly providing us with anti-LRP-1 antibody. We thank E. Lambert for helpful discussions and L. Debelle and S. Wright for editorial assistance.