LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities.
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.
Dedieu
Stéphane
S
CNRS UMR MEOyC 6237, Laboratoire SiRMA (Signalisation des Récepteurs Matriciels), Université de Reims Champagne-Ardenne, Moulin de la Housse, BP 1039, 51687 Reims Cedex 2, France. stephane.dedieu@univ-reims.fr
Langlois
Benoît
B
Devy
Jérôme
J
Sid
Brice
B
Henriet
Patrick
P
Sartelet
Hervé
H
Bellon
Georges
G
Emonard
Hervé
H
Martiny
Laurent
L
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape; D004705:Endocytosis; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D016608:Talin / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D051419:Paxillin; D011973:Receptors, LDL; D016608:Talin; D025521:Tumor Suppressor Proteins; C496077:Tln1 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2