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: Urša Pečar Fonović, Zala Jevnikar, Matija Rojnik, Bojan Doljak, Marko Fonović, Polona Jamnik, Janko Kos
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53918 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23326535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Ligands
• Profilins
• RNA, Small Interfering
• CTSK protein, human
• Cathepsin K

Topics

• Actins (metabolism)
• Cathepsin K (antagonists & inhibitors, genetics, metabolism)
• Cell Adhesion (genetics)
• Cell Line, Tumor
• Cell Membrane (metabolism, ultrastructure)
• Cell Movement (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Ligands
• Male
• Neoplasm Invasiveness (genetics)
• Profilins (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• RNA, Small Interfering