title: Nuclear translocation of a clusterin isoform is associated with induction of anoikis in SV40-immortalized human prostate epithelial cells.
abstract: Clusterin gene expression is potently induced in experimental models in which apoptosis is activated, such as rat prostate involution following castration. Nevertheless, its precise physiological role has not yet been established, and both anti-apoptotic and pro-apoptotic functions have been suggested for this gene. Clusterin expression level depends on cell proliferation state, and we recently showed that its over-expression inhibited cell cycle progression of SV40-immortalized human prostate epithelial cells PNT2 and PNT1a. Here we studied clusterin expression in PNT1a cells subjected to serum-starvation with the aim of defining clusterin early molecular changes following apoptosis induction. Under serum-starvation conditions, decreased growth rate, slow rounding-up of cells, cell detachment, and formation of apoptotic bodies indicative of anoikis (detachment-induced apoptosis) were preceded by significant downregulation of 70 kDa clusterin precursor and upregulation of 45-40 kDa isoforms. On the 8th day of serum-free culturing, only the higher molecular weight protein-band of about 45 kDa was clearly induced and accumulated in detached cells and apoptotic bodies in which PARP was activated. Anoikis was preceded by induction and transloction of a 45-kDa clusterin isoform to the nucleus. Thus, nuclear targeting of a specific 45-kDa isoform of clusterin appeared to be an early and specific molecular signal triggering anoikis-death. Considering also that clusterin is downregulated during prostate cancer onset and progression, and that its upregulation has inhibited DNA synthesis and cell cycle progression of immortalized human prostate epithelial cells, we suggest that clusterin might be a new anti-oncogene in the prostate.
authors.affiliation: Department of Medicina Sperimentale, University of Parma, 43100 Parma, Italy.
authors.forename: A E
authors.initials: AE
authors.lastname: Caccamo
authors.forename: M
authors.initials: M
authors.lastname: Scaltriti
authors.forename: A
authors.initials: A
authors.lastname: Caporali
authors.forename: D
authors.initials: D
authors.lastname: D'Arca
authors.forename: F
authors.initials: F
authors.lastname: Scorcioni
authors.forename: G
authors.initials: G
authors.lastname: Candiano
authors.forename: M
authors.initials: M
authors.lastname: Mangiola
authors.forename: S
authors.initials: S
authors.lastname: Bettuzzi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002472:Cell Transformation, Viral; D051152:Clusterin; D016895:Culture Media, Serum-Free; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D007700:Kinetics; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics*
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D007633:Keratins