Cell detachment and apoptosis induction of immortalized human prostate epithelial cells are associated with early accumulation of a 45 kDa nuclear isoform of clusterin.
Clusterin, ubiquitously distributed in mammalians, was cloned and identified as the most potently induced gene during rat prostate involution following androgen deprivation. Also found to be involved in many other patho-physiological processes, its biological significance is still controversial, particularly with regard to apoptosis. We previously showed that transient over-expression of clusterin blocked cell cycle progression of simian-virus-40-immortalized human prostate epithelial cell lines PNT1A and PNT2. We show in the present study that the accumulation of an intracellular 45 kDa clusterin isoform was an early event closely associated with death of PNT1A cells caused by cell detachment followed by apoptosis induction (anoikis). Cell morphological changes, decreased proliferation rate and cell cycle arrest at G0/G1-S-phase checkpoint were all strictly associated with the production and early translocation to the nucleus of a 45 kDa clusterin isoform. Later, nuclear clusterin was found accumulated in detached cells and apoptotic bodies. These results suggest that a 45 kDa isoform of clusterin, when targeted to the nucleus, can decrease cell proliferation and promotes cell-detachment-induced apoptosis, suggesting a possible major role for clusterin as an anti-proliferative gene in human prostate epithelial cells.
Caccamo
Alessandro E
AE
Dipartimento di Medicina Sperimentale, University of Parma, Via Volturno 39, 43100 Parma, Italy.
Scaltriti
Maurizio
M
Caporali
Andrea
A
D'Arca
Domenico
D
Scorcioni
Francesca
F
Astancolle
Serenella
S
Mangiola
Massimo
M
Bettuzzi
Saverio
S
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D023102:Anoikis / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002461:Cell Line, Transformed; D051152:Clusterin; D016895:Culture Media, Serum-Free / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D004847:Epithelial Cells / Q000737:chemistry* / Q000201:enzymology / Q000502:physiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005796:Genes / Q000502:physiology; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011467:Prostate / Q000166:cytology*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism
C495242:CLU protein, human; D051152:Clusterin; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; C024857:poly(ADP)-ribosylated proteins; D011064:Poly Adenosine Diphosphate Ribose; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020169:Caspases