title: Profilin 1 as a target for cathepsin X activity in tumor cells.
abstract: Cathepsin X has been reported to be a tumor promotion factor in various types of cancer; however, the molecular mechanisms linking its activity with malignant processes are not understood. Here we present profilin 1, a known tumor suppressor, as a target for cathepsin X carboxypeptidase activity in prostate cancer PC-3 cells. Profilin 1 co-localizes strongly with cathepsin X intracellularly in the perinuclear area as well as at the plasma membrane. Selective cleavage of C-terminal amino acids was demonstrated on a synthetic octapeptide representing the profilin C-terminal region, and on recombinant profilin 1. Further, intact profilin 1 binds its poly-L-proline ligand clathrin significantly better than it does the truncated one, as shown using cathepsin X specific inhibitor AMS-36 and immunoprecipitation of the profilin 1/clathrin complex. Moreover, the polymerization of actin, which depends also on the binding of poly-L-proline ligands to profilin 1, was promoted by AMS-36 treatment of cells and by siRNA cathepsin X silencing. Our results demonstrate that increased adhesion, migration and invasiveness of tumor cells depend on the inactivation of the tumor suppressive function of profilin 1 by cathepsin X. The latter is thus designated as a target for development of new antitumor strategies.
authors: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: Urša
authors: U
authors: Pečar Fonović
authors: Zala
authors: Z
authors: Jevnikar
authors: Matija
authors: M
authors: Rojnik
authors: Bojan
authors: B
authors: Doljak
authors: Marko
authors: M
authors: Fonović
authors: Polona
authors: P
authors: Jamnik
authors: Janko
authors: J
authors: Kos
mesh_terms: D000199:Actins / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D051304:Profilins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034741:RNA, Small Interfering
chemical_list: D000199:Actins; D008024:Ligands; D051304:Profilins; D034741:RNA, Small Interfering; C534130:CTSK protein, human; D056657:Cathepsin K