title: Nuclear clusterin accumulation during heat shock response: implications for cell survival and thermo-tolerance induction in immortalized and prostate cancer cells.
abstract: Clusterin (CLU), whose role is still debated, is differentially regulated in several patho-physiological processes and invariably induced during apoptosis. In heat shock response, CLU is considered a stress-inducible, pro-survival/cyto-protective factor via an HSE element present in his promoter. In both human prostate PNT1A and PC-3 epithelial cells we found that apoptotic stimuli induced nuclear localization of CLU (nCLU), and that overexpression of nCLU is pro-apoptotic. We show here that CLU time-course accumulation kinetic is different from that of HSP70 in these cells, thus other factor(s) might mediate HSF-1 activation and CLU expression. Sub-lethal heat shock inhibited the secretion of CLU (sCLU), leading to increased cytoplasm accumulation of CLU (cCLU) in association to cell survival. At difference, lethal heat stress caused massive accumulation of pro-apoptotic nCLU in cells dying by caspase-3-dependent apoptosis. Double heat stress (sub-lethal heat shock followed by recovery and lethal stress) induced HSP70 and thermo-tolerance in PNT1A cells, but not in PC-3 cells. In PNT1A cells, CLU secretion was inhibited and cCLU was accumulated, suggesting that cCLU might be pro-survival, while in PC-3 cells accumulation of nCLU was concomitant to caspase-3 induction and PARP activation instead. Thus, CLU expression/sub-cellular localization is strictly related to cell fate. In particular, nCLU and physiological levels of HSP70 affected cell survival in an antagonistic fashion. Prevalence of heat-induced nCLU, not allowing PC-3 cells to cope with heat shock, could be the rational explaining why malignant cells are more sensitive to heat when delivered by minimally invasive procedures for ablation of localized prostate cancer.
authors.affiliation: Dipartimento di Medicina Sperimentale, Sezione di Biochimica, Biochimica Clinica e Biochimica dell'Esercizio Fisico, Università di Parma, Via Volturno Parma, Italy.
authors.forename: Alessandro E
authors.initials: AE
authors.lastname: Caccamo
authors.forename: Silvia
authors.initials: S
authors.lastname: Desenzani
authors.forename: Lucia
authors.initials: L
authors.lastname: Belloni
authors.forename: Angelo F
authors.initials: AF
authors.lastname: Borghetti
authors.forename: Saverio
authors.initials: S
authors.lastname: Bettuzzi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006358:Hot Temperature; D006801:Humans; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051152:Clusterin; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases