title: Molecular mechanisms of the antimetastatic activity of nuclear clusterin in prostate cancer cells.
abstract: The proapoptotic activity of nuclear clusterin (nCLU) in cancer cells is now well established. We previously showed that nCLU decreases the motility of prostate cancer cells by triggering a dramatic dismantling of the actin cytoskeleton. Here, we sought to unravel the molecular mechanisms of the antimetastatic activity of nCLU. We found that nCLU: i) decreases LIMK1 expression, thus increasing the levels of the active (unphosphorylated) form of cofilin, the well known actin depolymerizing factor; ii) binds to vimentin, sequestering the protein from its adhesion sites at the cell periphery, thus interfering with its role in cell motility and adhesion; iii) affects the intracellular distribution of E-cadherin (the major component of epithelial adherens junctions) which appears to be diffusely distributed in the cells. Through these mechanisms nCLU reduces the migratory/invasive behavior of PC3 cells; this effect is further demonstrated by a decreased secretion of active MMP-2 from the cells. Thus, in addition to its proapoptotic function, nCLU also exerts a strong anti-migratory/anti-invasive activity in prostate cancer cells, by interfering with the cytoskeletal components and by decreasing MMP-2 activity.
authors.affiliation: Department of Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, I-20133 Milan, Italy.
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Moretti
authors.forename: Stefania
authors.initials: S
authors.lastname: Mai
authors.forename: Marina
authors.initials: M
authors.lastname: Montagnani Marelli
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzi
authors.forename: Saverio
authors.initials: S
authors.lastname: Bettuzzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Limonta
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D011485:Protein Binding; D021381:Protein Transport; D014162:Transfection; D014746:Vimentin / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D015820:Cadherins; D051152:Clusterin; D014746:Vimentin; C515892:LIMK1 protein, human; D054461:Lim Kinases; D020778:Matrix Metalloproteinase 2