title: Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells.
abstract: Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK-eIF2alpha (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2alpha: eucaryotic initiation factor 2alpha), ATFalpha (ATFalpha: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21(WAF)), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21(WAF) in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.
authors.affiliation: Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zu
authors.forename: T
authors.initials: T
authors.lastname: Bihani
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.forename: Y-M
authors.initials: YM
authors.lastname: Park
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.forename: C
authors.initials: C
authors.lastname: Ip
mesh_terms: D016203:CDC2 Protein Kinase / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000502:physiology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017510:Protein Folding; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016203:CDC2 Protein Kinase; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016566:Organoselenium Compounds; D051742:Transcription Factor CHOP; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C008493:methylselenic acid